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Kopsky DJ, Vrancken AFJE, van Eijk RPA, Alvarez-Jimenez R, Szadek KM, Liebregts R, Steegers MAH. Fast Analgesic Effect in Response Test with Topical Phenytoin Cream Correlates with Prolonged Pain Relief After Extended Use in Painful Diabetic Neuropathy. Pharmaceuticals (Basel) 2025; 18:228. [PMID: 40006041 PMCID: PMC11858914 DOI: 10.3390/ph18020228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/14/2025] [Accepted: 01/24/2025] [Indexed: 02/27/2025] Open
Abstract
Background: Treatment of painful diabetic neuropathy (PDN) poses several challenges due to the limited effectiveness, high incidence of side effects, and potential drug interactions of oral neuropathic pain medication. Lacking systemic side effects, topical phenytoin cream offers a promising innovative approach to addressing unmet needs in neuropathic pain treatment. In this retrospective study in patients with PDN, we evaluated the analgesic effect of topical phenytoin cream in response tests and after extended use. Methods: We collected data from PDN patients who, prior to prolonged use of phenytoin 10% or 20% cream, either had an open response test (ORET), a single-blind (SIBRET), or a double-blind (DOBRET) placebo-controlled response test with phenytoin cream between November 2016 and February 2023. A positive ORET was defined as pain reduction of at least two points on the 11-point numerical scale (NRS) within 30 min after phenytoin cream application. A positive SIBRET or DOBRET required an additional pain reduction of 1 NRS point in the phenytoin treated area compared to the placebo. In patients with a positive response test, we evaluated the sustained pain reduction and the proportion of patients experiencing minimum pain relief of at least 30% (MPR30: moderate pain relief) and 50% (MPR50: considerable pain relief) after the extended use of phenytoin cream. We also assessed the correlation between the response test analgesic effect and the sustained pain relief. Results: We identified 65 patients with PDN of whom 31 (47.7%) had a positive response test. The median pain reduction in response tests was 3.0 NRS points (IQR 2.0-4.0). Extended use (median 3.3 months, IQR 1.5-12.1]) resulted in a median pain reduction of 4.0 NRS points (IQR 3.0-5.0); 26/31 (83.9%) of patients achieved MPR30, and 21/31 (67.7%) MPR50 achieved pain relief. The response test analgesic effect correlated significantly with sustained pain relief after extended use (τ = 0.72, p < 0.0001). Conclusions: In PDN patients who had a positive phenytoin cream response test, extended use of phenytoin cream provided a significant sustained pain relief.
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Affiliation(s)
- David J. Kopsky
- Anesthesiology and Pain Management, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; (R.A.-J.); (K.M.S.); (M.A.H.S.)
- Institute for Neuropathic Pain, 1056 SN Amsterdam, The Netherlands
- Department of Neurology, Brain Centre University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
| | - Alexander F. J. E. Vrancken
- Department of Neurology, Brain Centre University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
| | - Ruben P. A. van Eijk
- Department of Neurology, Brain Centre University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
- Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Ricardo Alvarez-Jimenez
- Anesthesiology and Pain Management, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; (R.A.-J.); (K.M.S.); (M.A.H.S.)
| | - Karolina M. Szadek
- Anesthesiology and Pain Management, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; (R.A.-J.); (K.M.S.); (M.A.H.S.)
| | - Remko Liebregts
- Anesthesiology and Pain Management, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; (R.A.-J.); (K.M.S.); (M.A.H.S.)
| | - Monique A. H. Steegers
- Anesthesiology and Pain Management, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; (R.A.-J.); (K.M.S.); (M.A.H.S.)
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Elbeddini A, Tanvir A, Yilmaz O, Rahman Y, Mongon R. Assessing the efficacy of topical formulations in diabetic neuropathy: a narrative review. J Diabetes Metab Disord 2024; 23:1613-1620. [PMID: 39610558 PMCID: PMC11599498 DOI: 10.1007/s40200-024-01459-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 06/19/2024] [Indexed: 11/30/2024]
Abstract
Background We conducted a review of topical medications available for alleviation of diabetic neuropathic pain (DNP) and compared their efficacy with oral medications for pain relief. We also explored the feasibility of compounding topical medications. Methods Searches on PubMed, Medline Ovid, and Embase databases were conducted and findings were presented as a narrative review. Results and discussion 8% Capsaicin patches and 5% Lidocaine patches had the most evidence. The literature also showed evidence for topical clonidine, gabapentin, and amitriptyline. Conclusion Topical formulations are a potential substitute to oral medications in patients suffering from DNP. Potential options include 8% Capsaicin patch, 5% Lidocaine patch, Clonidine gel, Topical gabapentin, and an amitriptyline and ketamine combination. A promising area of research that requires further study is the effect of a combination of topicals in alleviated DNP.
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Affiliation(s)
- Ali Elbeddini
- Family Medicine Department, University of Ottawa, School of Medicine, 600 Peter Morand Crescent Suite 201, Ottawa, ON K1G 5Z3 Canada
| | - Azasma Tanvir
- College of Medicine, University of Saskatchewan, 107 Wiggins Rd, Saskatoon, SK S7N 5E5 Canada
| | - Orhan Yilmaz
- College of Medicine, University of Saskatchewan, 107 Wiggins Rd, Saskatoon, SK S7N 5E5 Canada
| | - Yusra Rahman
- Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8 Canada
| | - Renata Mongon
- Anesthesiology Department, State University of Campinas, Campinas, Brazil
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Marchesi N, Fahmideh F, Pascale A, Allegri M, Govoni S. Neuropathic Pain in Aged People: An Unresolved Issue Open to Novel Drug Approaches, Focusing on Painful Diabetic Neuropathy. Curr Neuropharmacol 2024; 22:53-64. [PMID: 37550909 PMCID: PMC10716885 DOI: 10.2174/1570159x21666230807103642] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/17/2023] [Accepted: 03/15/2023] [Indexed: 08/09/2023] Open
Abstract
A majority of older patients suffer from neuropathic pain (NP) that significantly alters their daily activities and imposes a significant burden on health care. Multiple comorbidities and the risk of polypharmacy in the elderly make it challenging to determine the appropriate drug, dosage, and maintenance of therapy. Age-dependent processes play a contributing role in neuropathy given that diabetic neuropathy (DN) is the most common form of neuropathy. This narrative review is mainly focused on the drug treatment approach for neuropathy-associated pain in aged people including both drugs and dietary supplements, considering the latter as add-on mechanism-based treatments to increase the effectiveness of usual treatments by implementing their activity or activating other analgesic pathways. On one hand, the limited clinical studies assessing the effectiveness and the adverse effects of existing pain management options in this age segment of the population (> 65), on the other hand, the expanding global demographics of the elderly contribute to building up an unresolved pain management problem that needs the attention of healthcare providers, researchers, and health authorities as well as the expansion of the current therapeutic options.
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Affiliation(s)
- Nicoletta Marchesi
- Department of Drug Sciences, Section of Pharmacology, University of Pavia, Pavia, Italy
| | - Foroogh Fahmideh
- Department of Drug Sciences, Section of Pharmacology, University of Pavia, Pavia, Italy
| | - Alessia Pascale
- Department of Drug Sciences, Section of Pharmacology, University of Pavia, Pavia, Italy
| | - Massimo Allegri
- Ensemble Hospitalier de la Cote - Centre Lemanique d'antalgie et Neuromodulation, Morges, Switzerland
| | - Stefano Govoni
- Department of Drug Sciences, Section of Pharmacology, University of Pavia, Pavia, Italy
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4
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Hassanzadeh S, Bagheri S, Majid Ahmadi S, Ahmadi SA, Moradishibany I, Dolatkhah H, Reisi S. Effectiveness of oral clonidine and gabapentin on peripheral neuropathy in diabetic patients in southwestern Iran: a randomized clinical trial. BMC Endocr Disord 2023; 23:224. [PMID: 37845651 PMCID: PMC10577942 DOI: 10.1186/s12902-023-01486-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 10/11/2023] [Indexed: 10/18/2023] Open
Abstract
BACKGROUND Peripheral neuropathy is not only the most prevalent consequence of diabetes but also the main reason for foot ulceration, disability, and amputation. Therefore, the current study aims to determine the effectiveness of oral clonidine and gabapentin on peripheral neuropathy in diabetic patients. METHODS This 12-week, randomized, and parallel-group trial was conducted to compare the efficacy of oral clonidine and gabapentin with gabapentin alone in diabetic patients in southwest Iran during the first half of 2021. Thirty patients with type 2 diabetes with peripheral neuropathy as assessed by a visual analog scale (VAS) and divided into two groups of 15 patients, treated for up to three months. The data were analyzed using SPSS-21 software. In order to report the results, descriptive indices, independent t-test, one-way analysis of covariance (ANCOVA) and analysis of variance with repeated measures were used. RESULTS The mean and standard deviation of the age of the participants in the clonidine + gabapentin group was equal to 50.20 ± 7.44, and in the gabapentin group was equal to 50.47 ± 7.57 (t = 0.10, P-value = 0.923). This research showed a significant difference between the clonidine + gabapentin group and with gabapentin group in terms of neuropathic pain and the severity of neuropathic pain (P < 0.001). CONCLUSIONS According to this research results, clonidine + gabapentin can reduce neuropathic pain and the severity of neuropathic pain in diabetic patients. Therefore, it is recommended that healthcare professionals with diabetes expertise prescribe these medications to reduce neuropathic pain and its severity. TRIAL REGISTRATION This study was registered in the Iranian Clinical Trials System with the ID (IRCT20211106052983N1) on 14/01/2022.
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Affiliation(s)
- Sajad Hassanzadeh
- Department of Internal Medicine, School of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Soraya Bagheri
- Department of Internal Medicine, School of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Seyed Majid Ahmadi
- Department of Internal Medicine, School of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran.
| | | | - Isaac Moradishibany
- Department of Internal Medicine, School of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Hosein Dolatkhah
- Department of Internal Medicine, School of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Sajjad Reisi
- Genetic and Environmental Adventures Research Center, School of Abarkouh Paramedicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Ismail CAN. Issues and challenges in diabetic neuropathy management: A narrative review. World J Diabetes 2023; 14:741-757. [PMID: 37383599 PMCID: PMC10294062 DOI: 10.4239/wjd.v14.i6.741] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/24/2023] [Accepted: 04/11/2023] [Indexed: 06/14/2023] Open
Abstract
Diabetic neuropathy (DN) is a devastating disorder with an increasing prevalence globally. This epidemic can pose a critical burden on individuals and com-munities, subsequently affecting the productivity and economic output of a country. With more people living a sedentary lifestyle, the incidence of DN is escalating worldwide. Many researchers have relentlessly worked on ways to combat this devastating disease. Their efforts have given rise to a number of commercially available therapies that can alleviate the symptoms of DN. Unfortunately, most of these therapies are only partially effective. Worse still, some are associated with unfavorable side effects. This narrative review aims to highlight current issues and challenges in the management of DN, especially from the perspective of molecular mechanisms that lead to its progression, with the hope of providing future direction in the management of DN. To improve the approaches to diabetic management, the suggested resolutions in the literature are also discussed in this review. This review will provide an in-depth understanding of the causative mechanisms of DN, apart from the insights to improve the quality and strategic approaches to DN management.
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Affiliation(s)
- Che Aishah Nazariah Ismail
- Department of Physiology, School of Medical Sciences, University Sains Malaysia Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
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Preston FG, Riley DR, Azmi S, Alam U. Painful Diabetic Peripheral Neuropathy: Practical Guidance and Challenges for Clinical Management. Diabetes Metab Syndr Obes 2023; 16:1595-1612. [PMID: 37288250 PMCID: PMC10243347 DOI: 10.2147/dmso.s370050] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/16/2023] [Indexed: 06/09/2023] Open
Abstract
Painful diabetic peripheral neuropathy (PDPN) is present in nearly a quarter of people with diabetes. It is estimated to affect over 100 million people worldwide. PDPN is associated with impaired daily functioning, depression, sleep disturbance, financial instability, and a decreased quality of life. Despite its high prevalence and significant health burden, it remains an underdiagnosed and undertreated condition. PDPN is a complex pain phenomenon with the experience of pain associated with and exacerbated by poor sleep and low mood. A holistic approach to patient-centred care alongside the pharmacological therapy is required to maximise benefit. A key treatment challenge is managing patient expectation, as a good outcome from treatment is defined as a reduction in pain of 30-50%, with a complete pain-free outcome being rare. The future for the treatment of PDPN holds promise, despite a 20-year void in the licensing of new analgesic agents for neuropathic pain. There are over 50 new molecular entities reaching clinical development and several demonstrating benefit in early-stage clinical trials. We review the current approaches to its diagnosis, the tools, and questionnaires available to clinicians, international guidance on PDPN management, and existing pharmacological and non-pharmacological treatment options. We synthesise evidence and the guidance from the American Association of Clinical Endocrinology, American Academy of Neurology, American Diabetes Association, Diabetes Canada, German Diabetes Association, and the International Diabetes Federation into a practical guide to the treatment of PDPN and highlight the need for future research into mechanistic-based treatments in order to prioritise the development of personalised medicine.
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Affiliation(s)
- Frank G Preston
- Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool, Liverpool, UK
| | - David R Riley
- Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool, Liverpool, UK
| | - Shazli Azmi
- Institute of Cardiovascular Science, University of Manchester and Manchester Diabetes Centre, Manchester Foundation Trust, Manchester, UK
| | - Uazman Alam
- Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool, Liverpool, UK
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool, UK
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Wasim R, Ansari TM, Siddiqui MH, Ahsan F, Shamim A, Singh A, Shariq M, Anwar A, Siddiqui AR, Parveen S. Repurposing of Drugs for Cardiometabolic Disorders: An Out and Out Cumulation. Horm Metab Res 2023; 55:7-24. [PMID: 36599357 DOI: 10.1055/a-1971-6965] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Cardiometabolic disorders (CMD) is a constellation of metabolic predisposing factors for atherosclerosis such as insulin resistance (IR) or diabetes mellitus (DM), systemic hypertension, central obesity, and dyslipidemia. Cardiometabolic diseases (CMDs) continue to be the leading cause of mortality in both developed and developing nations, accounting for over 32% of all fatalities globally each year. Furthermore, dyslipidemia, angina, arrhythmia, heart failure, myocardial infarction (MI), and diabetes mellitus are the major causes of death, accounting for an estimated 19 million deaths in 2012. CVDs will kill more than 23 million individuals each year by 2030. Nonetheless, new drug development (NDD) in CMDs has been increasingly difficult in recent decades due to increased costs and a lower success rate. Drug repositioning in CMDs looks promising in this scenario for launching current medicines for new therapeutic indications. Repositioning is an ancient method that dates back to the 1960s and is mostly based on coincidental findings during medication trials. One significant advantage of repositioning is that the drug's safety profile is well known, lowering the odds of failure owing to undesirable toxic effects. Furthermore, repositioning takes less time and money than NDD. Given these facts, pharmaceutical corporations are becoming more interested in medication repositioning. In this follow-up, we discussed the notion of repositioning and provided some examples of repositioned medications in cardiometabolic disorders.
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Affiliation(s)
| | | | | | - Farogh Ahsan
- Pharmacology, Integral University, Lucknow, India
| | | | - Aditya Singh
- Pharmaceutics, Integral University, Lucknow, India
| | | | - Aamir Anwar
- Pharmacy, Integral University, Lucknow, India
| | | | - Saba Parveen
- Pharmacology, Integral University, Lucknow, India
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Kemp HI, Vollert J, Davies NWS, Moyle GJ, Rice ASC. A Comparison of Self-reported Pain Measures Between Sensory Phenotypes in HIV-associated Sensory Neuropathy. THE JOURNAL OF PAIN 2023; 24:112-127. [PMID: 36116766 DOI: 10.1016/j.jpain.2022.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 07/30/2022] [Accepted: 09/01/2022] [Indexed: 02/08/2023]
Abstract
Painful HIV-associated neuropathy (HIV-SN) is a prevalent co-morbidity of HIV infection. Sensory phenotyping, using quantitative sensory testing (QST) could allow for improved stratification to guide personalized treatment. However, previous methods of QST interpretation have demonstrated limited association with self-reported pain measures. This study sought to identify differences in self-reported pain measures between composite QST-derived sensory phenotypes, and to examine any differences in participants reporting multi-site, multi-etiology chronic pain. In this cross-sectional observational study of participants with HIV (n = 133), individuals were allocated to neuropathy and neuropathic pain groups through clinical assessment and nerve conduction testing. They completed symptom-based questionnaires and underwent standardized QST. Participants were assigned, by pre-determined algorithm, to a QST-derived sensory phenotype. Symptoms were compared between sensory phenotypes. Symptom characteristics and Neuropathic Pain Symptom Inventory scores differed between QST-derived sensory phenotypes: 'sensory loss' was associated with more paroxysmal and paraesthetic symptoms compared to 'thermal hyperalgesia' and 'healthy' phenotypes (P = .023-0.001). Those with painful HIV-SN and additional chronic pain diagnoses were more frequently allocated to the 'mechanical hyperalgesia' phenotype compared to those with painful HIV-SN alone (P = .006). This study describes heterogeneous sensory phenotypes in people living with HIV. Differences in self-reported pain outcomes between sensory phenotypes has the potential to guide future stratified trials and eventually more targeted therapy. PERSPECTIVE: This article presents quantitative sensory testing derived phenotypes, thought to reflect differing pathophysiological pain mechanisms and relates them to self-reported pain measures in people with HIV infection. This could help clinicians stratify patients to individualize analgesic interventions more effectively.
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Affiliation(s)
- Harriet I Kemp
- Pain Research Group, Imperial College London, London, UK.
| | - Jan Vollert
- Pain Research Group, Imperial College London, London, UK; Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital of Schleswig-Holstein, Campus Kiel, Germany; Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Germany; Neurophysiology, Mannheim Center of Translational Neuroscience (MCTN), Medical Faculty Mannheim, Heidelberg University, Germany
| | - Nicholas W S Davies
- Department of Neurology, Chelsea & Westminster NHS Foundation Trust, London, UK
| | - Graeme J Moyle
- Department of HIV Medicine, Chelsea & Westminster NHS Foundation Trust, London, UK
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9
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Kopsky DJ, van Eijk RPA, Warendorf JK, Keppel Hesselink JM, Notermans NC, Vrancken AFJE. Enriched enrollment randomized double-blind placebo-controlled cross-over trial with phenytoin cream in painful chronic idiopathic axonal polyneuropathy (EPHENE): a study protocol. Trials 2022; 23:888. [PMID: 36273216 PMCID: PMC9587538 DOI: 10.1186/s13063-022-06806-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 09/30/2022] [Indexed: 11/10/2022] Open
Abstract
Background Patients with chronic idiopathic axonal polyneuropathy (CIAP) can have neuropathic pain that significantly impacts quality of life. Oral neuropathic pain medication often has insufficient pain relief and side effects. Topical phenytoin cream could circumvent these limitations. The primary objectives of this trial are to evaluate (1) efficacy in pain reduction and (2) safety of phenytoin cream in patients with painful CIAP. The main secondary objective is to explore the usefulness of a double-blind placebo-controlled response test (DOBRET) to identify responders to sustained pain relief with phenytoin cream. Methods This 6-week, enriched enrollment randomized double-blind, placebo-controlled triple cross-over trial compares phenytoin 20%, 10% and placebo cream in 48 participants with painful CIAP. Enriched enrollment is based on a positive DOBRET in 48 participants who experience within 30 minutes ≥2 points pain reduction on the 11-point numerical rating scale (NRS) in the phenytoin 10% cream applied area and ≥1 point difference in pain reduction on the NRS between phenytoin 10% and placebo cream applied area, in favour of the former. To explore whether DOBRET has predictive value for sustained pain relief, 24 DOBRET-negative participants will be included. An open-label extension phase is offered with phenytoin 20% cream for up to one year, to study long-term safety. The main inclusion criteria are a diagnosis of CIAP and symmetrical neuropathic pain with a mean weekly pain score of ≥4 and <10 on the NRS. The primary outcome is the mean difference between phenytoin 20% versus placebo cream in 7-day average pain intensity, as measured by the NRS, over week 2 in DOBRET positive participants. Key secondary outcomes include the mean difference in pain intensity between phenytoin 10% and phenytoin 20% cream, and between phenytoin 10% and placebo cream. Furthermore, differences between the 3 interventions will be evaluated on the Neuropathic Pain Symptom Inventory, EuroQol EQ5-5D-5L, and evaluation of adverse events. Discussion This study will provide evidence on the efficacy and safety of phenytoin cream in patients with painful CIAP and will give insight into the usefulness of DOBRET as a way of personalized medicine to identify responders to sustained pain relief with phenytoin cream. Trial registration ClinicalTrials.gov NCT04647877. Registered on 1 December 2020.
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Affiliation(s)
- David J Kopsky
- Institute for Neuropathic Pain, Amsterdam / Soest / Bosch en Duin, The Netherlands. .,Department of Neurology, Brain Centre University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
| | - Ruben P A van Eijk
- Department of Neurology, Brain Centre University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.,Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Janna K Warendorf
- Department of Neurology, Brain Centre University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | | | - Nicolette C Notermans
- Department of Neurology, Brain Centre University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Alexander F J E Vrancken
- Department of Neurology, Brain Centre University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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10
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Gewandter JS, Sohn MB, De Guzman R, Frazer ME, Chiodo V, Sharma S, Geha P, Markman JD. Predicting Treatment Response with Sensory Phenotyping in Post-Traumatic Neuropathic Pain. PAIN MEDICINE (MALDEN, MASS.) 2022; 23:1726-1732. [PMID: 35312012 PMCID: PMC9527609 DOI: 10.1093/pm/pnac045] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 03/07/2022] [Accepted: 03/10/2022] [Indexed: 11/12/2022]
Abstract
OBJECTIVE Currently available treatments for neuropathic pain are only modestly efficacious when assessed in randomized clinical trials and work for only some patients in the clinic. Induced-pain or gain-of-function phenotypes have been shown to predict response to analgesics (vs placebos) in patients with neuropathic pain. However, the predictive value of these phenotypes has never been studied in post-traumatic neuropathic pain. METHODS Mixed-effects models for repeated measures were used to evaluate the efficacy of pregabalin vs placebo in subgroups with induced-pain phenotypes (i.e., hyperalgesia or allodynia) in data from a recent, multinational randomized clinical trial (N = 539) that identified phenotypic subgroups through the use of a structured clinical exam. RESULTS The difference in mean pain score between the active and placebo groups (i.e., delta) after 15 weeks of treatment for the subgroup with hyperalgesia was -0.76 (P = 0.001), compared with 0.19 (P = 0.47) for the subgroup that did not have hyperalgesia. The treatment-by-phenotype interaction, which tests whether subgroups have statistically different treatment responses, was significant (P = 0.0067). The delta for the subgroup with allodynia was -0.31 (P = 0.22), compared with -0.30 (P = 0.22) for the subgroup that did not have allodynia (treatment-by-phenotype interaction P = 0.98). CONCLUSIONS These data suggest that hyperalgesia, but not allodynia, predicts response to pregabalin in patients with chronic post-traumatic neuropathic pain. This study extends the growing data supporting the utility of induced-pain phenotypes to predict response to analgesics in post-traumatic neuropathic pain. Sensory phenotyping in large, multisite trials through the use of a structured clinical exam has the potential to accelerate the development of new analgesics and improve the generalizability of clinical trial results.
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Affiliation(s)
- Jennifer S Gewandter
- Correspondence to: Jennifer S. Gewandter, PhD, MPH, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box 604, Rochester, NY 14642, USA. Tel: 585-276-5661; Fax: 585-244-7271; E-mail:
| | - Michael B Sohn
- Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York
| | - Rachel De Guzman
- Department of Neurosurgery, University of Rochester, Rochester, New York
| | - Maria E Frazer
- Department of Neurosurgery, University of Rochester, Rochester, New York
| | - Valerie Chiodo
- Department of Neurosurgery, University of Rochester, Rochester, New York
| | - Sonia Sharma
- Department of Oral Diagnostic Sciences, University at Buffalo School of Dental Medicine, Buffalo, New York
| | - Paul Geha
- Department of Psychiatry, University of Rochester, Rochester, New York, USA
| | - John D Markman
- Department of Neurosurgery, University of Rochester, Rochester, New York
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11
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Dludla PV, Nkambule BB, Cirilli I, Marcheggiani F, Mabhida SE, Ziqubu K, Ntamo Y, Jack B, Nyambuya TM, Hanser S, Mazibuko-Mbeje SE. Capsaicin, its clinical significance in patients with painful diabetic neuropathy. Biomed Pharmacother 2022; 153:113439. [DOI: 10.1016/j.biopha.2022.113439] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 12/14/2022] Open
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A comparative study of Botulinum toxin type A versus conventional oral therapy as a second-line treatment of diabetic neuropathy. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2022. [DOI: 10.1186/s41983-022-00527-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Diabetes mellitus is commonly complicated by diabetic peripheral neuropathy. Poor adherence to medication is common in diabetic peripheral neuropathy mainly due to common side effects and poor tolerance to medication. Botulinum toxin A intradermal injection has proved efficacy in cases of diabetic peripheral neuropathy, however there is a need to compare its effect to other lines of treatment. The aim of the study was to compare Botulinum toxin type A versus conventional oral treatment as a second-line treatment of painful diabetic peripheral neuropathy. The current study was a comparative study on 30 patients with type 2 diabetes mellitus. Diabetic peripheral neuropathy was proved by nerve conduction study. All patients were on carbamazepine. Patients were divided randomly into three groups. First group was add-on duloxetine, second group was add-on gabapentin and the third group was injected intradermal with Botulinum toxin A.
Results
Our study showed that Botulinum A intradermal injection, gabapentin and duloxetine add-on therapy decreased the VAS and PSQI over a 12-week study period and this was statistically significant at p < 0.001*. Botulinum A intradermal injection also decreased the mean of PSQ1 from 17.3 ± 1.8 to 10.9 ± 3.1 in 12 weeks constituting the highest decline in PSQ1 among the three groups and this was statistically significant at p < 0.001*.
Conclusion
Botulinum toxin A injection had a comparable if not superior efficacy to duloxetine and gabapentin as a second-line treatment of diabetic peripheral neuropathy.
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Smith S, Normahani P, Lane T, Hohenschurz-Schmidt D, Oliver N, Davies AH. Prevention and Management Strategies for Diabetic Neuropathy. LIFE (BASEL, SWITZERLAND) 2022; 12:life12081185. [PMID: 36013364 PMCID: PMC9410148 DOI: 10.3390/life12081185] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/17/2022] [Accepted: 07/28/2022] [Indexed: 11/16/2022]
Abstract
Diabetic neuropathy (DN) is a common complication of diabetes that is becoming an increasing concern as the prevalence of diabetes rapidly rises. There are several types of DN, but the most prevalent and studied type is distal symmetrical polyneuropathy, which is the focus of this review and is simply referred to as DN. It can lead to a wide range of sensorimotor and psychosocial symptoms and is a major risk factor for diabetic foot ulceration and Charcot neuropathic osteoarthropathy, which are associated with high rates of lower limb amputation and mortality. The prevention and management of DN are thus critical, and clinical guidelines recommend several strategies for these based on the best available evidence. This article aims to provide a narrative review of DN prevention and management strategies by discussing these guidelines and the evidence that supports them. First, the epidemiology and diverse clinical manifestations of DN are summarized. Then, prevention strategies such as glycemic control, lifestyle modifications and footcare are discussed, as well as the importance of early diagnosis. Finally, neuropathic pain management strategies and promising novel therapies under investigation such as neuromodulation devices and nutraceuticals are reviewed.
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Affiliation(s)
- Sasha Smith
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Pasha Normahani
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Tristan Lane
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Department of Vascular Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
| | - David Hohenschurz-Schmidt
- Pain Research Group, Department of Surgery and Cancer, Imperial College London, London SW10 9NH, UK;
| | - Nick Oliver
- Section of Metabolic Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W2 1PG, UK;
- Division of Medicine and Integrated Care, Imperial College Healthcare NHS Trust, London W2 1NY, UK
| | - Alun Huw Davies
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London W6 8RF, UK
- Correspondence:
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Serednicki WT, Wrzosek A, Woron J, Garlicki J, Dobrogowski J, Jakowicka-Wordliczek J, Wordliczek J, Zajaczkowska R. Topical clonidine for neuropathic pain in adults. Cochrane Database Syst Rev 2022; 5:CD010967. [PMID: 35587172 PMCID: PMC9119025 DOI: 10.1002/14651858.cd010967.pub3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Clonidine is a presynaptic alpha-2-adrenergic receptor agonist that has been used for many years to treat hypertension and other conditions, including chronic pain. Adverse events associated with systemic use of the drug have limited its application. Topical use of drugs has been gaining interest since the beginning of the century, as it may limit adverse events without loss of analgesic efficacy. Topical clonidine (TC) formulations have been investigated for almost 20 years in clinical trials. This is an update of the original Cochrane Review published in Issue 8, 2015. OBJECTIVES The objective of this review was to assess the analgesic efficacy and safety of TC compared with placebo or other drugs in adults aged 18 years or above with chronic neuropathic pain. SEARCH METHODS For this update we searched the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid), and Embase (Ovid) databases, and reference lists of retrieved papers and trial registries. We also contacted experts in the field. The most recent search was performed on 27 October 2021. SELECTION CRITERIA We included randomised, double-blind studies of at least two weeks' duration comparing TC versus placebo or other active treatment in adults with chronic neuropathic pain. DATA COLLECTION AND ANALYSIS Two review authors independently screened references for eligibility, extracted data, and assessed risk of bias. Any discrepancies were resolved by discussion or by consulting a third review author if necessary. Where required, we contacted trial authors to request additional information. We presented pooled estimates for dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) with P values. We used Review Manager Web software to perform the meta-analyses. We used a fixed-effect model if we considered heterogeneity as not important; otherwise, we used a random-effects model. The review primary outcomes were: participant-reported pain relief of 50% or greater; participant-reported pain relief of 30% or greater; much or very much improved on Patient Global Impression of Change scale (PGIC); and very much improved on PGIC. Secondary outcomes included withdrawals due to adverse events; participants experiencing at least one adverse event; and withdrawals due to lack of efficacy. All outcomes were measured at the longest follow-up period. We assessed the certainty of evidence using GRADE and created two summary of findings tables. MAIN RESULTS We included four studies in the review (two new in this update), with a total of 743 participants with painful diabetic neuropathy (PDN). TC (0.1% or 0.2%) was applied in gel form to the painful area two to three times daily. The double-blind treatment phase of three studies lasted 8 weeks to 85 days and compared TC versus placebo. In the fourth study, the double-blind treatment phase lasted 12 weeks and compared TC versus topical capsaicin. We assessed the studies as at unclear or high risk of bias for most domains; all studies were at unclear risk of bias for allocation concealment and blinding of outcome assessment; one study was at high risk of bias for blinding of participants and personnel; two studies were at high risk of attrition bias; and three studies were at high risk of bias due to notable funding concerns. We judged the certainty of evidence (GRADE) to be moderate to very low, downgrading for study limitations, imprecision of results, and publication bias. TC compared to placebo There was no evidence of a difference in number of participants with participant-reported pain relief of 50% or greater during longest follow-up period (12 weeks) between groups (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.78 to 1.86; 179 participants; 1 study; low certainty evidence). However, the number of participants with participant-reported pain relief of 30% or greater during longest follow-up period (8 to 12 weeks) was higher in the TC group compared with placebo (RR 1.35, 95% CI 1.03 to 1.77; 344 participants; 2 studies, very low certainty evidence). The number needed to treat for an additional beneficial outcome (NNTB) for this comparison was 8.33 (95% CI 4.3 to 50.0). Also, there was no evidence of a difference between groups for the outcomes much or very much improved on the PGIC during longest follow-up period (12 weeks) or very much improved on PGIC during the longest follow-up period (12 weeks) (RR 1.06, 95% CI 0.76 to 1.49 and RR 1.82, 95% CI 0.89 to 3.72, respectively; 179 participants; 1 study; low certainty evidence). We observed no evidence of a difference between groups in withdrawals due to adverse events and withdrawals due to lack of efficacy during the longest follow-up period (12 weeks) (RR 0.34, 95% CI 0.04 to 3.18 and RR 1.01, 95% CI 0.06 to 15.92, respectively; 179 participants; 1 study; low certainty evidence) and participants experiencing at least one adverse event during longest follow-up period (12 weeks) (RR 0.65, 95% CI 0.14 to 3.05; 344 participants; 2 studies; low certainty evidence). TC compared to active comparator There was no evidence of a difference in the number of participants with participant-reported pain relief of 50% or greater during longest follow-up period (12 weeks) between groups (RR 1.41, 95% CI 0.99 to 2.0; 139 participants; 1 study; low certainty evidence). Other outcomes were not reported. AUTHORS' CONCLUSIONS This is an update of a review published in 2015, for which our conclusions remain unchanged. Topical clonidine may provide some benefit to adults with painful diabetic neuropathy; however, the evidence is very uncertain. Additional trials are needed to assess TC in other neuropathic pain conditions and to determine whether it is possible to predict who or which groups of people will benefit from TC.
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Affiliation(s)
- Wojciech T Serednicki
- Department of Interdisciplinary Intensive Care, Jagiellonian University Collegium Medicum, Krakow, Poland
- University Hospital, Krakow, Poland
| | - Anna Wrzosek
- Department of Interdisciplinary Intensive Care, Jagiellonian University Collegium Medicum, Krakow, Poland
- University Hospital, Krakow, Poland
| | - Jaroslaw Woron
- Department of Interdisciplinary Intensive Care, Jagiellonian University Collegium Medicum, Krakow, Poland
- University Hospital, Krakow, Poland
| | - Jaroslaw Garlicki
- Department of Interdisciplinary Intensive Care, Jagiellonian University Collegium Medicum, Krakow, Poland
- University Hospital, Krakow, Poland
| | - Jan Dobrogowski
- Department of Interdisciplinary Intensive Care, Jagiellonian University Collegium Medicum, Krakow, Poland
- University Hospital, Krakow, Poland
| | - Joanna Jakowicka-Wordliczek
- Department of Interdisciplinary Intensive Care, Jagiellonian University Collegium Medicum, Krakow, Poland
- University Hospital, Krakow, Poland
| | - Jerzy Wordliczek
- Department of Interdisciplinary Intensive Care, Jagiellonian University Collegium Medicum, Krakow, Poland
- University Hospital, Krakow, Poland
| | - Renata Zajaczkowska
- Department of Interdisciplinary Intensive Care, Jagiellonian University Collegium Medicum, Krakow, Poland
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Staudt MD, Prabhala T, Sheldon BL, Quaranta N, Zakher M, Bhullar R, Pilitsis JG, Argoff CE. Current Strategies for the Management of Painful Diabetic Neuropathy. J Diabetes Sci Technol 2022; 16:341-352. [PMID: 32856490 PMCID: PMC8861791 DOI: 10.1177/1932296820951829] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The development of painful diabetic neuropathy (PDN) is a common complication of chronic diabetes that can be associated with significant disability and healthcare costs. Prompt symptom identification and aggressive glycemic control is essential in controlling the development of neuropathic complications; however, adequate pain relief remains challenging and there are considerable unmet needs in this patient population. Although guidelines have been established regarding the pharmacological management of PDN, pain control is inadequate or refractory in a high proportion of patients. Pharmacotherapy with anticonvulsants (pregabalin, gabapentin) and antidepressants (duloxetine) are common first-line agents. The use of oral opioids is associated with considerable morbidity and mortality and can also lead to opioid-induced hyperalgesia. Their use is therefore discouraged. There is an emerging role for neuromodulation treatment modalities including intrathecal drug delivery, spinal cord stimulation, and dorsal root ganglion stimulation. Furthermore, consideration of holistic alternative therapies such as yoga and acupuncture may augment a multidisciplinary treatment approach. This aim of this review is to focus on the current management strategies for the treatment of PDN, with a discussion of treatment rationale and practical considerations for their implementation.
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Affiliation(s)
- Michael D Staudt
- Department of Neurosurgery, Albany Medical College, Albany, New York, USA
| | - Tarun Prabhala
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany NY, USA
| | - Breanna L Sheldon
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany NY, USA
| | - Nicholas Quaranta
- Department of Anesthesiology, Albany Medical College, Albany, New York, USA
| | - Michael Zakher
- Department of Anesthesiology, Albany Medical College, Albany, New York, USA
| | - Ravneet Bhullar
- Department of Anesthesiology, Albany Medical College, Albany, New York, USA
| | - Julie G Pilitsis
- Department of Neurosurgery, Albany Medical College, Albany, New York, USA
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany NY, USA
| | - Charles E Argoff
- Department of Neurology, Albany Medical College, Albany, New York, USA
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16
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Amiri A, Esmailian M, Golshani K, Tavakolifard N. Effects of adding oral clonidine to standard treatments on pain intensity of patients with acute renal colic: A randomized clinical trial. Adv Biomed Res 2022; 11:28. [PMID: 35720212 PMCID: PMC9201228 DOI: 10.4103/abr.abr_2_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 03/15/2021] [Accepted: 05/15/2021] [Indexed: 11/18/2022] Open
Abstract
Background: The aim of this study was to compare the effect of adding oral clonidine to standard treatments on pain intensity in patients with acute renal colic. Materials and Methods: This is a randomized clinical trial that was performed in 2020 in Isfahan. The study population consisted of 200 patients with renal colic. Pain of the patients was assessed using Visual Analog Scale. Patients were then randomized into 4 groups of 50 patients. Group A received 0.1 mg/kg morphine and clonidine tablets (0.2 mg). Group B received morphine and placebo. Group C received 30 mg ketorolac and clonidine tablets. Group D received 30 mg ketorolac and placebo tablets. Pain of patients was assessed. 0.05 mg/kg morphine was administered and repeated every 40 min if the pain was not reduced. Results: Our data showed that there was a significant difference between pains of patient by the time of admission in groups (P = 0.04). However, no significant differences were observed between pains of patients in different measuring times (P > 0.05). Using general linear model, we showed that the decreases in pain scores of each group were significant (P < 0.05) but there were no significant differences in pains of patients in different measuring times (P > 0.05). Our data showed that Group A and Group C had lowest frequencies of morphine administrations while Groups B and D had the highest frequencies (P < 0.001). Conclusion: We showed that administration of clonidine in patients with renal colic resulted in better pain control and lower morphine injections.
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17
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Sloan G, Alam U, Selvarajah D, Tesfaye S. The Treatment of Painful Diabetic Neuropathy. Curr Diabetes Rev 2022; 18:e070721194556. [PMID: 34238163 DOI: 10.2174/1573399817666210707112413] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/18/2021] [Accepted: 03/08/2021] [Indexed: 11/22/2022]
Abstract
Painful diabetic peripheral neuropathy (painful-DPN) is a highly prevalent and disabling condition, affecting up to one-third of patients with diabetes. This condition can have a profound impact resulting in a poor quality of life, disruption of employment, impaired sleep, and poor mental health with an excess of depression and anxiety. The management of painful-DPN poses a great challenge. Unfortunately, currently there are no Food and Drug Administration (USA) approved disease-modifying treatments for diabetic peripheral neuropathy (DPN) as trials of putative pathogenetic treatments have failed at phase 3 clinical trial stage. Therefore, the focus of managing painful- DPN other than improving glycaemic control and cardiovascular risk factor modification is treating symptoms. The recommended treatments based on expert international consensus for painful- DPN have remained essentially unchanged for the last decade. Both the serotonin re-uptake inhibitor (SNRI) duloxetine and α2δ ligand pregabalin have the most robust evidence for treating painful-DPN. The weak opioids (e.g. tapentadol and tramadol, both of which have an SNRI effect), tricyclic antidepressants such as amitriptyline and α2δ ligand gabapentin are also widely recommended and prescribed agents. Opioids (except tramadol and tapentadol), should be prescribed with caution in view of the lack of definitive data surrounding efficacy, concerns surrounding addiction and adverse events. Recently, emerging therapies have gained local licenses, including the α2δ ligand mirogabalin (Japan) and the high dose 8% capsaicin patch (FDA and Europe). The management of refractory painful-DPN is difficult; specialist pain services may offer off-label therapies (e.g. botulinum toxin, intravenous lidocaine and spinal cord stimulation), although there is limited clinical trial evidence supporting their use. Additionally, despite combination therapy being commonly used clinically, there is little evidence supporting this practise. There is a need for further clinical trials to assess novel therapeutic agents, optimal combination therapy and existing agents to determine which are the most effective for the treatment of painful-DPN. This article reviews the evidence for the treatment of painful-DPN, including emerging treatment strategies such as novel compounds and stratification of patients according to individual characteristics (e.g. pain phenotype, neuroimaging and genotype) to improve treatment responses.
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Affiliation(s)
- Gordon Sloan
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
| | - Uazman Alam
- Department of Cardiovascular and Metabolic Medicine and the Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool, and Liverpool University Hospital, NHS Foundation Trust, Liverpool, UK
- Division of Diabetes, Endocrinology and Gastroenterology, Institute of Human Development, University of Manchester, Manchester, UK
| | - Dinesh Selvarajah
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, UK
| | - Solomon Tesfaye
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
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James CF, Tripathi S, Karampatou K, Gladston DV, Pappachan JM. Pharmacotherapy of Painful Diabetic Neuropathy: A Clinical Update. SISLI ETFAL HASTANESI TIP BULTENI 2022; 56:1-20. [PMID: 35515975 PMCID: PMC9040305 DOI: 10.14744/semb.2021.54670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 12/30/2021] [Indexed: 02/08/2023]
Abstract
The rising prevalence of diabetes mellitus (DM) leads on to an increase in chronic diabetic complications. Diabetic peripheral neuropathies (DPNs) are common chronic complications of diabetes. Distal symmetric polyneuropathy is the most prevalent form. Most patients with DPN will remain pain-free; however, painful DPN (PDPN) occurs in 6-34% of all DM patients and is associated with reduced health-related-quality-of-life and substantial economic burden. Symptomatic treatment of PDPN and diabetic autonomic neuropathy is the key treatment goals. Using certain patient related characteristics, subjects with PDPN can be stratified and assigned targeted therapies to produce better pain outcomes. The aim of this review is to discuss the various pathogenetic mechanisms of DPN with special reference to the mechanisms leading to PDPN and the various pharmacological and non-pharmacological therapies available for its management. Recommended pharmacological therapies include anticonvulsants, antidepressants, opioid analgesics, and topical medications.
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Affiliation(s)
- Cornelius Fernandez James
- Department of Endocrinology & Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, United Kingdom
| | - Shiva Tripathi
- Department of Anaesthesia & Pain Management, Lancashire Teaching Hospitals NHS Trust, United Kingdom
| | - Kyriaki Karampatou
- Department of Endocrinology & Metabolism, Lancashire Teaching Hospitals NHS Trust, United Kingdom
| | - Divya V Gladston
- Department of Anaesthesiology, Regional Cancer Centre, Thiruvananthapuram, India
| | - Joseph M Pappachan
- Department of Endocrinology & Metabolism, Lancashire Teaching Hospitals NHS Trust, United Kingdom; The University of Manchester, Manchester, UK; Manchester Metropolitan University, Manchester, UK
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Jingxuan L, Litian M, Jianfang F. Different Drugs for the Treatment of Painful Diabetic Peripheral Neuropathy: A Meta-Analysis. Front Neurol 2021; 12:682244. [PMID: 34777192 PMCID: PMC8585758 DOI: 10.3389/fneur.2021.682244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 10/04/2021] [Indexed: 01/16/2023] Open
Abstract
Objective: To systematically evaluate the effects of different drugs for the treatment of painful diabetic peripheral neuropathy. Methods: All literature from PubMed, Embase, and Cochrane Central Register of Controlled Trials published over the past 12 years (from January 1, 2008 to June 1, 2020) was searched, and two reviewers independently assessed study eligibility, continuous data extraction, independent assessment of bias risk, and graded strength of evidence. The pain score was used as the main result, and 30 and 50% pain reduction and adverse events were used as secondary results. Results: A total of 37 studies were included. Pregabalin, duloxetine, tapentadol, lacosamide, mirogabalin, and capsaicin were all more effective than placebo in alleviating the pain associated with diabetic peripheral neuropathy, while ABT-894 and gabapentin showed no significant effect. In addition, the efficacy of buprenorphine, tanezumab, fulranumab and others could not be concluded due to insufficient studies. Conclusion: Pregabalin and duloxetine showed good therapeutic effects on painful DPN, but adverse events were also significant. The analgesic effects of ABT-894 and gabapentin need to be further studied with longer and larger RCTs. As an opioid drug, tapentadol has a good analgesic effect, but due to its addiction, it needs to be very cautious in clinical use. Although lacosamide, mirogabalin, and capsaicin are more effective than placebo, the therapeutic effect is weaker than pregabalin. For the results of our meta-analysis, long-term studies are still needed to verify their efficacy and safety in the future. Systematic Review Registration: PROSPERO, identifier: CRD42020197397.
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Affiliation(s)
- Lian Jingxuan
- Department of Endocrinology, Xijing Hospital of Air Force Medical University, Xi'an, China
| | - Ma Litian
- Department of Gastroenterology, Xijing Hospital of Air Force Medical University, Xi'an, China
| | - Fu Jianfang
- Department of Endocrinology, Xijing Hospital of Air Force Medical University, Xi'an, China
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Todorovic MS, Frey K, Swarm RA, Bottros M, Rao L, Tallchief D, Kraus K, Meacham K, Bakos K, Zang X, Lee JB, Kagan L, Haroutounian S. Prediction of Individual Analgesic Response to Intravenous Lidocaine in Painful Diabetic Peripheral Neuropathy: A Randomized, Placebo-controlled, Crossover Trial. Clin J Pain 2021; 38:65-76. [PMID: 34723864 PMCID: PMC8727500 DOI: 10.1097/ajp.0000000000001001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 07/19/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVES Intravenous lidocaine can alleviate painful diabetic peripheral neuropathy (DPN) in some patients. Whether quantitative sensory testing (QST) can identify treatment responders has not been prospectively tested. MATERIALS AND METHODS This was a prospective, randomized, double-blind, crossover, placebo-controlled trial comparing intravenous lidocaine to normal saline (placebo) for painful DPN. Thirty-four participants with painful DPN were enrolled and administered intravenous lidocaine (5 mg/kg ideal body weight) or placebo as a 40-minute infusion, after a battery of QST parameters were tested on the dorsal foot, with a 3-week washout period between infusions. RESULTS Thirty-one participants completed both study sessions and were included in the final analysis. Lidocaine resulted in a 51% pain reduction 60 to 120 minutes after infusion initiation, as assessed on a 0 to 10 numerical rating scale, while placebo resulted in a 33.5% pain reduction (difference=17.6%, 95% confidence interval [CI], 1.9%-33.3%, P=0.03). Neither mechanical pain threshold, heat pain threshold, or any of the other measured QST parameters predicted the response to treatment. Lidocaine administration reduced mean Neuropathic Pain Symptom Inventory paresthesia/dysesthesia scores when compared with placebo by 1.29 points (95% CI, -2.03 to -0.55, P=0.001), and paroxysmal pain scores by 0.84 points (95% CI, -1.62 to -0.56, P=0.04), without significant changes in burning, pressing or evoked pain subscores. DISCUSSION While some participants reported therapeutic benefit from lidocaine administration, QST measures alone were not predictive of response to treatment. Further studies, powered to test more complex phenotypic interactions, are required to identify reliable predictors of response to pharmacotherapy in patients with DPN.
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Affiliation(s)
| | - Karen Frey
- Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA, 63110
| | - Robert A. Swarm
- Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA, 63110
- Washington University Pain Center, St Louis, MO, USA, 63110
| | - Michael Bottros
- Department of Anesthesiology, Keck School of Medicine of USC, Los Angeles, CA, 90033
| | - Lesley Rao
- Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA, 63110
- Washington University Pain Center, St Louis, MO, USA, 63110
| | - Danielle Tallchief
- Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA, 63110
| | - Kristin Kraus
- Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA, 63110
| | - Kathleen Meacham
- Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA, 63110
- Washington University Pain Center, St Louis, MO, USA, 63110
| | - Kristopher Bakos
- Investigational Drug Service, Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, MO, USA
| | - Xiaowei Zang
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, NJ, USA, 08854
| | - Jong Bong Lee
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, NJ, USA, 08854
| | - Leonid Kagan
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, NJ, USA, 08854
- Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, NJ, USA, 08854
| | - Simon Haroutounian
- Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA, 63110
- Washington University Pain Center, St Louis, MO, USA, 63110
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21
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Casale R. Capsaicin 179-mg cutaneous patch in the treatment of post-surgical neuropathic pain: a scoping review of current evidence and place in therapy. Expert Rev Neurother 2021; 21:1147-1158. [PMID: 34461799 DOI: 10.1080/14737175.2021.1974842] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/27/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION The use of topical agents has been suggested for post-surgical neuropathic pain. A high-concentration capsaicin 179-mg cutaneous patch (Qutenza™) is licensed in adults for chronic neuropathic pain in the EU, and neuropathic pain with post-herpetic neuralgia and neuropathic pain with diabetic peripheral neuropathy in the USA. This article aims to describe the use of a topical capsaicin 179-mg cutaneous patch in the treatment of PSNP. AREA COVERED This narrative review presents the relevant clinical aspects of the use of a topical capsaicin 179-mg cutaneous patch for the treatment of post-surgical neuropathic pain (PSNP). Randomized control trials, observational studies, case series, and reports investigating the clinical use of the capsaicin patch were searched through MEDLINE, EMBASE, AMED, Cochrane Library, CINAHL, Web of Science, and ROAD databases. Trials from citation lists of reviewed articles and hand-searching were added. The search concluded in September 2020. 10/20 articles were considered. EXPERT OPINION Some clinical studies demonstrated the efficacy of the capsaicin 179-mg patch in PSNP as monotherapy and concomitant treatment with oral treatments. This topical treatment of PSNP is better tolerated and accepted compared with systemic treatments. To maximize the effectiveness of the treatment, correct administration recommendations should be followed.
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Affiliation(s)
- Roberto Casale
- Opusmedica Persons, Care & Research - PC&R, Piacenza, Italy
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22
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Quesada C, Kostenko A, Ho I, Leone C, Nochi Z, Stouffs A, Wittayer M, Caspani O, Brix Finnerup N, Mouraux A, Pickering G, Tracey I, Truini A, Treede RD, Garcia-Larrea L. Human surrogate models of central sensitization: A critical review and practical guide. Eur J Pain 2021; 25:1389-1428. [PMID: 33759294 PMCID: PMC8360051 DOI: 10.1002/ejp.1768] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 03/17/2021] [Accepted: 03/21/2021] [Indexed: 12/11/2022]
Abstract
Background As in other fields of medicine, development of new medications for management of neuropathic pain has been difficult since preclinical rodent models do not necessarily translate to the clinics. Aside from ongoing pain with burning or shock‐like qualities, neuropathic pain is often characterized by pain hypersensitivity (hyperalgesia and allodynia), most often towards mechanical stimuli, reflecting sensitization of neural transmission. Data treatment We therefore performed a systematic literature review (PubMed‐Medline, Cochrane, WoS, ClinicalTrials) and semi‐quantitative meta‐analysis of human pain models that aim to induce central sensitization, and generate hyperalgesia surrounding a real or simulated injury. Results From an initial set of 1569 reports, we identified and analysed 269 studies using more than a dozen human models of sensitization. Five of these models (intradermal or topical capsaicin, low‐ or high‐frequency electrical stimulation, thermode‐induced heat‐injury) were found to reliably induce secondary hyperalgesia to pinprick and have been implemented in multiple laboratories. The ability of these models to induce dynamic mechanical allodynia was however substantially lower. The proportion of subjects who developed hypersensitivity was rarely provided, giving rise to significant reporting bias. In four of these models pharmacological profiles allowed to verify similarity to some clinical conditions, and therefore may inform basic research for new drug development. Conclusions While there is no single “optimal” model of central sensitization, the range of validated and easy‐to‐use procedures in humans should be able to inform preclinical researchers on helpful potential biomarkers, thereby narrowing the translation gap between basic and clinical data. Significance Being able to mimic aspects of pathological pain directly in humans has a huge potential to understand pathophysiology and provide animal research with translatable biomarkers for drug development. One group of human surrogate models has proven to have excellent predictive validity: they respond to clinically active medications and do not respond to clinically inactive medications, including some that worked in animals but failed in the clinics. They should therefore inform basic research for new drug development.
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Affiliation(s)
- Charles Quesada
- NeuroPain lab, Lyon Centre for Neuroscience Inserm U1028, Lyon, France.,Pain Center Neurological Hospital (CETD), Hospices Civils de Lyon, Lyon, France
| | - Anna Kostenko
- Department of Neurophysiology, Mannheim center for Translational Neurosciences, Heidelberg University, Heidelberg, Germany
| | - Idy Ho
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Caterina Leone
- Department of Human Neuroscience, Sapienza University, Rome, Italy
| | - Zahra Nochi
- Danish Pain Research Center, Dept of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Alexandre Stouffs
- Institute of Neuroscience (IoNS), Université Catholique de Louvain (UCLouvain), Ottignies-Louvain-la-Neuve, Belgium
| | - Matthias Wittayer
- Department of Neurophysiology, Mannheim center for Translational Neurosciences, Heidelberg University, Heidelberg, Germany
| | - Ombretta Caspani
- Department of Neurophysiology, Mannheim center for Translational Neurosciences, Heidelberg University, Heidelberg, Germany
| | - Nanna Brix Finnerup
- Danish Pain Research Center, Dept of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - André Mouraux
- Institute of Neuroscience (IoNS), Université Catholique de Louvain (UCLouvain), Ottignies-Louvain-la-Neuve, Belgium
| | | | - Irene Tracey
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Andrea Truini
- Department of Human Neuroscience, Sapienza University, Rome, Italy
| | - Rolf-Detlef Treede
- Department of Neurophysiology, Mannheim center for Translational Neurosciences, Heidelberg University, Heidelberg, Germany
| | - Luis Garcia-Larrea
- NeuroPain lab, Lyon Centre for Neuroscience Inserm U1028, Lyon, France.,Pain Center Neurological Hospital (CETD), Hospices Civils de Lyon, Lyon, France
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23
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Topical Treatments and Their Molecular/Cellular Mechanisms in Patients with Peripheral Neuropathic Pain-Narrative Review. Pharmaceutics 2021; 13:pharmaceutics13040450. [PMID: 33810493 PMCID: PMC8067282 DOI: 10.3390/pharmaceutics13040450] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/17/2021] [Accepted: 03/22/2021] [Indexed: 12/25/2022] Open
Abstract
Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients' quality of life, as pharmacological and non-pharmacological methods often fail or induce side effects. Topical treatments are gaining popularity in the management of peripheral neuropathic pain, due to excellent safety profiles and preferences. Moreover, topical treatments applied locally may target the underlying mechanisms of peripheral sensitization and pain. Recent studies showed that peripheral sensitization results from interactions between neuronal and non-neuronal cells, with numerous signaling molecules and molecular/cellular targets involved. This narrative review discusses the molecular/cellular mechanisms of drugs available in topical formulations utilized in clinical practice and their effectiveness in clinical studies in patients with peripheral neuropathic pain. We searched PubMed for papers published from 1 January 1995 to 30 November 2020. The key search phrases for identifying potentially relevant articles were "topical AND pain", "topical AND neuropathic", "topical AND treatment", "topical AND mechanism", "peripheral neuropathic", and "mechanism". The result of our search was 23 randomized controlled trials (RCT), 9 open-label studies, 16 retrospective studies, 20 case (series) reports, 8 systematic reviews, 66 narrative reviews, and 140 experimental studies. The data from preclinical studies revealed that active compounds of topical treatments exert multiple mechanisms of action, directly or indirectly modulating ion channels, receptors, proteins, and enzymes expressed by neuronal and non-neuronal cells, and thus contributing to antinociception. However, which mechanisms and the extent to which the mechanisms contribute to pain relief observed in humans remain unclear. The evidence from RCTs and reviews supports 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A injections as effective treatments in patients with peripheral neuropathic pain. In turn, single RCTs support evidence of doxepin, funapide, diclofenac, baclofen, clonidine, loperamide, and cannabidiol in neuropathic pain states. Topical administration of phenytoin, ambroxol, and prazosin is supported by observational clinical studies. For topical amitriptyline, menthol, and gabapentin, evidence comes from case reports and case series. For topical ketamine and baclofen, data supporting their effectiveness are provided by both single RCTs and case series. The discussed data from clinical studies and observations support the usefulness of topical treatments in neuropathic pain management. This review may help clinicians in making decisions regarding whether and which topical treatment may be a beneficial option, particularly in frail patients not tolerating systemic pharmacotherapy.
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24
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Kemp HI, Kennedy DL, Vollert J, Davies NWS, Scott W, Rice ASC. Chronic pain and cognitive impairment: a cross-sectional study in people living with HIV. AIDS Care 2021:1-14. [PMID: 33739206 DOI: 10.1080/09540121.2021.1902934] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Cognitive impairment and chronic pain are amongst the most prevalent neurological sequelae of HIV infection, yet little is understood about the potential bidirectional relationship between the two conditions. Cognitive dysfunction can occur in chronic pain populations whilst those with cognitive impairment can display modified responses to experimentally induced painful stimuli. To date, this has not been explored in HIV cohorts.This study aimed to identify any contribution of chronic pain to cognitive impairment in HIV and to determine differences in pain characteristics between those with and without cognitive dysfunction.This was an observational cohort study involving people living with HIV (n = 148) in the United Kingdom. Participants underwent validated questionnaire-based measurement of pain severity, interference and symptom quality as well as conditioned pain modulation and quantitative sensory testing. All participants completed a computer-based cognitive function assessment.Fifty-seven participants met the criteria for cognitive impairment and 73 for chronic pain. The cognitive impairment group had a higher prevalence of chronic pain (p = 0.004) and reported more neuropathic symptoms (p = 0.001). Those with chronic pain performed less well in emotional recognition and verbal learning domains. The interaction identified between chronic pain and cognitive dysfunction warrants further exploration to identify causal links or shared pathology.
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Affiliation(s)
- Harriet I Kemp
- Pain Research Group, Department of Surgery & Cancer, Imperial College London, London, UK
| | - Donna L Kennedy
- Pain Research Group, Department of Surgery & Cancer, Imperial College London, London, UK
| | - Jan Vollert
- Pain Research Group, Department of Surgery & Cancer, Imperial College London, London, UK
| | - Nicholas W S Davies
- Department of Neurology, Chelsea & Westminster NHS Foundation Trust, London, UK
| | - Whitney Scott
- Health Psychology Section, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.,INPUT Pain Management Unit, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Andrew S C Rice
- Pain Research Group, Department of Surgery & Cancer, Imperial College London, London, UK
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25
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Fulas OA, Laferrière A, Ware DMA, Shir Y, Coderre TJ. The effect of a topical combination of clonidine and pentoxifylline on post-traumatic neuropathic pain patients: study protocol for a randomized, double-blind placebo-controlled trial. Trials 2021; 22:149. [PMID: 33596969 PMCID: PMC7890866 DOI: 10.1186/s13063-021-05088-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 02/01/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND First-line pharmacotherapy for neuropathic pain entails the use of systemic antidepressants and anticonvulsants. These drugs are not optimally effective and poorly tolerated, especially for older patients with comorbid conditions. Given the high number of such patients, there is a need for a greater repertoire of safer and more effective analgesics. Clonidine and pentoxifylline are vasodilator agents that work synergistically to enhance tissue perfusion and oxygenation. The topical administration of these drugs, individually and in combination, has shown anti-nociceptive properties in rodent models of neuropathic pain. A topically-administered combination of clonidine and pentoxifylline also effectively reduced the intensity of both spontaneous and evoked pain in healthy volunteers with experimentally-induced neuropathic pain. The next step in advancing this formulation to clinical use is the undertaking of a phase II clinical study to assess its efficacy and safety in neuropathic pain patients. METHODS/DESIGN This is a study protocol for a randomized, double-blind, placebo-controlled, phase II clinical trial with a cross-over design. It is a single-centered, 5-week study that will enroll a total of 32 patients with post-traumatic peripheral neuropathic pain. Patients will be treated topically with either a combination of clonidine and pentoxifylline or placebo for a period of 2 weeks each, in randomly assigned order across patients, with an intervening washout period of 1 week. The primary outcome measures of the study are the intensity of spontaneous pain recorded daily in a pain diary with a visual analog scale, and the degree of mechanical allodynia evoked by a brush stimulus. The secondary outcome measures of the study include scores of pain relief and change in the area of punctate hyperalgesia. This trial has been prospectively registered with ClinicalTrials.gov on November 1, 2017. ClinicalTrials.gov Identifier: NCT03342950 . DISCUSSION The analgesic use of topical treatment with clonidine and pentoxifylline in combination has not been investigated in post-traumatic neuropathic pain. This study could generate the first evidence for the efficacy and safety of the formulation in alleviating pain in patients with neuropathic pain. Furthermore, this trial will provide objective grounds for the investigation of other agents that enhance tissue oxygenation in the topical treatment of peripheral neuropathic pain. TRIAL REGISTRATION This trial has been registered with ClinicalTrials.gov owned by NIH's US National Library of Medicine. ClinicalTrials.gov NCT03342950 . Registered on November 1, 2017 (trial was prospectively registered). PROTOCOL VERSION AND IDENTIFIERS This is protocol version 5, dated June 2018. McGill University Health Center (MUHC) Reaseach Ethics Board (REB) identification number: TTNP 2018-3906.
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Affiliation(s)
- Oli Abate Fulas
- Department of Anesthesia, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada
| | - André Laferrière
- Department of Anesthesia, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada
| | - D Mark A Ware
- Alan Edwards Pain Management Unit, McGill University Health Centre, 1650 Cedar Avenue, Montreal, QC, H3G 1A4, Canada
| | - Yoram Shir
- Alan Edwards Pain Management Unit, McGill University Health Centre, 1650 Cedar Avenue, Montreal, QC, H3G 1A4, Canada
| | - Terence J Coderre
- Department of Anesthesia, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada.
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26
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Sankarasubramanian V, Chiravuri S, Mirzakhalili E, Anaya CJ, Scott JR, Brummett CM, Clauw DJ, Patil PG, Harte SE, Lempka SF. Quantitative Sensory Testing of Spinal Cord and Dorsal Root Ganglion Stimulation in Chronic Pain Patients. Neuromodulation 2021; 24:672-684. [PMID: 33471409 DOI: 10.1111/ner.13329] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/17/2020] [Accepted: 11/10/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND/OBJECTIVES The physiological mechanisms underlying the pain-modulatory effects of clinical neurostimulation therapies, such as spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRGS), are only partially understood. In this pilot prospective study, we used patient-reported outcomes (PROs) and quantitative sensory testing (QST) to investigate the physiological effects and possible mechanisms of action of SCS and DRGS therapies. MATERIALS AND METHODS We tested 16 chronic pain patients selected for SCS and DRGS therapy, before and after treatment. PROs included pain intensity, pain-related symptoms (e.g., pain interference, pain coping, sleep interference) and disability, and general health status. QST included assessments of vibration detection theshold (VDT), pressure pain threshold (PPT) and tolerance (PPToL), temporal summation (TS), and conditioned pain modulation (CPM), at the most painful site. RESULTS Following treatment, all participants reported significant improvements in PROs (e.g., reduced pain intensity [p < 0.001], pain-related functional impairment [or pain interference] and disability [p = 0.001 for both]; better pain coping [p = 0.03], sleep [p = 0.002]), and overall health [p = 0.005]). QST showed a significant treatment-induced increase in PPT (p = 0.002) and PPToL (p = 0.011), and a significant reduction in TS (p = 0.033) at the most painful site, but showed no effects on VDT and CPM. We detected possible associations between a few QST measures and a few PROs. Notably, higher TS was associated with increased pain interference scores at pre-treatment (r = 0.772, p = 0.009), and a reduction in TS was associated with the reduction in pain interference (r = 0.669, p = 0.034) and pain disability (r = 0.690, p = 0.027) scores with treatment. CONCLUSIONS Our preliminary findings suggest significant clinical and therapeutic benefits associated with SCS and DRGS therapies, and the possible ability of these therapies to modulate pain processing within the central nervous system. Replication of our pilot findings in future, larger studies is necessary to characterize the physiological mechanisms of SCS and DRGS therapies.
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Affiliation(s)
- Vishwanath Sankarasubramanian
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.,Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA
| | - Srinivas Chiravuri
- Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
| | - Ehsan Mirzakhalili
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.,Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA
| | - Carlos J Anaya
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.,Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA
| | - John Ryan Scott
- Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
| | - Chad M Brummett
- Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
| | - Daniel J Clauw
- Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.,Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA
| | - Parag G Patil
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.,Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.,Department of Neurological Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Steven E Harte
- Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.,Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA
| | - Scott F Lempka
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.,Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.,Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
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27
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Abstract
BACKGROUND Diabetic neuropathy is a multifaceted condition affecting up to 50% of individuals with long standing diabetes. The most common presentation is peripheral diabetic sensory neuropathy (DPN). METHODS We carried out a systematic review of papers dealing with diabetic neuropathy on Pubmed in addition to a targeted Google search.Search terms included small fiber neuropathy,diffuse peripheral neuropathy, quantitative sensory testing, nerve conduction testing, intra-epidermal nerve fiber density, corneal confocal reflectance microscopy, aldose reductase inhbitors, nerve growth factor, alpha-lipoic acid, ruboxistaurin, nerve growth factor antibody, and cibinetide. RESULTS Over the past half century, there have been a number of agents undergoing unsuccessful trials for treatment of DPN.There are several approved agents for relief of pain caused by diabetic neuropathy, but these do not affect the pathologic process. EXPERT OPINION The failure to find treatments for diabetic neuropathy can be ascribed to (1) the complexity of design of studies and (2) the slow progression of the condition, necessitating long duration trials to prove efficacy.We propose a modification of the regulatory process to permit early introduction of agents with demonstrated safety and suggestion of benefit as well as prolongation of marketing exclusivity while long term trials are in progress to prove efficacy.
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Affiliation(s)
- Marc S Rendell
- The Association for Diabetes Investigators , Newport Coast, California. USA
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28
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Rastogi A, Jude EB. Novel treatment modalities for painful diabetic neuropathy. Diabetes Metab Syndr 2021; 15:287-293. [PMID: 33484985 DOI: 10.1016/j.dsx.2021.01.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 01/01/2021] [Accepted: 01/02/2021] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIMS Painful diabetic neuropathy significantly affects the quality of life in people with diabetic peripheral neuropathy (DPN). Existing pharmacological agents have limited efficacy and development of tolerance is a limitation. METHODS The present review focuses on novel pharmacological (systemic and topical) and non-pharmacological modalities for the alleviation of pain in people with DPN. We identified English language articles concerning studies with novel agents (animal or human) targeting symptomatic relief of painful diabetic neuropathy. RESULTS Though the pathophysiology of pain in DPN is complex, a better understanding of pain pathways (peripheral and central) have helped to identify potential targets for therapeutic success. Studies of pharmacological agents acting on various aspects of pain pathways including μ-opioid receptor agonist- norepinephrine reuptake inhibitor (MONRI), cannabinoid receptor, dual serotonin-nor-adrenergic (SNRI)-and triple dopamine reuptake inhibitor (SNDRI), purinergic receptors and sodium channel v1.7 blockers have undergone trials in humans and shown to improve pain symptoms and quality of life in people with DPN. A few other investigational agents targeting acetylcholine receptor, vanilloid channel, chemokine signaling, micro-RNA or mesenchymal stem cell based therapies (animal studies) have demonstrated promise in alleviation of pain. Topical agents like high-dose lidocaine, capsaicin, clonidine, amitriptyline and ketamine may benefit refractory neuropathic pain. CONCLUSIONS Novel MONRI, SNRI and cannabinoid receptor agonists have shown some promise for neuropathic pain relief in human trials, but await regulatory approvals. However, most of the novel pharmacological agents (systemic or topical) require appropriately powered placebo-controlled studies for clinical usage in painful diabetic neuropathy.
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Affiliation(s)
- A Rastogi
- Foot Care Division, Department of Endocrinology and Metabolism, PGIMER, Chandigarh, 160012, India.
| | - E B Jude
- Diabetes and Endocrinology Department, Tameside and Glossop Integrated Care NHS FT, Ashton Under Lyne, Lancs, OL69RW, UK
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29
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Abstract
There is tremendous interpatient variability in the response to analgesic therapy
(even for efficacious treatments), which can be the source of great frustration
in clinical practice. This has led to calls for “precision
medicine” or personalized pain therapeutics (ie, empirically based
algorithms that determine the optimal treatments, or treatment combinations, for
individual patients) that would presumably improve both the clinical care of
patients with pain and the success rates for putative analgesic drugs in phase 2
and 3 clinical trials. However, before implementing this approach, the
characteristics of individual patients or subgroups of patients that increase or
decrease the response to a specific treatment need to be identified. The
challenge is to identify the measurable phenotypic characteristics of patients
that are most predictive of individual variation in analgesic treatment
outcomes, and the measurement tools that are best suited to evaluate these
characteristics. In this article, we present evidence on the most promising of
these phenotypic characteristics for use in future research, including
psychosocial factors, symptom characteristics, sleep patterns, responses to
noxious stimulation, endogenous pain-modulatory processes, and response to
pharmacologic challenge. We provide evidence-based recommendations for core
phenotyping domains and recommend measures of each domain.
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30
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Yoon SY, Roh DH, Yeo JH, Woo J, Han SH, Kim KS. Analgesic Efficacy of α 2 Adrenergic Receptor Agonists Depends on the Chronic State of Neuropathic Pain: Role of Regulator of G Protein Signaling 4. Neuroscience 2020; 455:177-194. [PMID: 33359660 DOI: 10.1016/j.neuroscience.2020.12.021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 12/12/2020] [Accepted: 12/14/2020] [Indexed: 12/16/2022]
Abstract
The analgesic effect of alpha-2 adrenergic receptor (α2AR) agonists, which relieve chronic neuropathic pain, is highly variable among individuals. Here, we used a mouse model of spared nerve injury (SNI) to show that treatment time after the establishment of neuropathic pain was important for the variability in the analgesic efficacy of α2AR agonists, which was related to the activity of regulator of G-protein signaling protein 4 (RGS4). Intrathecal treatment with α2AR agonists, clonidine (0.1-1 nmol) or dexmedetomidine (0.3-1 nmol), relieved mechanical allodynia and thermal hyperalgesia on postoperative day (POD) 14, but their efficacy was weaker on POD28 and absent on POD56. The RGS4 level of plasma membrane was increased on POD56 compared to that on POD14. Moreover, in RGS4-deficient or RGS4 inhibitor (CCG50014)-treated mice, the analgesic effect of the α2AR agonists was conserved even on POD56. The increased plasma membrane RGS4 expression and the reduced level of active Gαi after clonidine injection on POD56 were completely restored by CCG50014. Higher doses of clonidine (10 nmol) and dexmedetomidine (3 nmol) relieved neuropathic pain on POD56 but were accompanied with serious side effects. Whereas, the coadministration of CCG50014 with clonidine (1 nmol) or dexmedetomidine (1 nmol) did not cause side effects. These findings demonstrated that SNI-induced increase in plasma membrane RGS4 expression was associated with low efficacy of α2AR agonists in a model of persistent, chronic neuropathic pain. Furthermore, α2AR agonist administration together with RGS4-targeted intervention represents a novel strategy for the treatment of neuropathic pain to overcome dose-limiting side effects.
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Affiliation(s)
- Seo-Yeon Yoon
- Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; College of Korean Medicine, Dongshin University, Gunjae Road 185, Naju-si, Jeonnam 58245, Republic of Korea.
| | - Dae-Hyun Roh
- Department of Oral Physiology, School of Dentistry, Kyung Hee University, Seoul 02454, Republic of Korea
| | - Ji-Hee Yeo
- Department of Oral Physiology, School of Dentistry, Kyung Hee University, Seoul 02454, Republic of Korea
| | - Jiwan Woo
- Research Animal Resource Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
| | - Se Hee Han
- Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
| | - Key-Sun Kim
- Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Research Animal Resource Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
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31
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Eagles DA, Chow CY, King GF. Fifteen years of Na
V
1.7 channels as an analgesic target: Why has excellent in vitro pharmacology not translated into in vivo analgesic efficacy? Br J Pharmacol 2020; 179:3592-3611. [DOI: 10.1111/bph.15327] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/14/2020] [Accepted: 10/23/2020] [Indexed: 12/16/2022] Open
Affiliation(s)
- David A. Eagles
- Institute for Molecular Bioscience The University of Queensland St Lucia QLD Australia
| | - Chun Yuen Chow
- Institute for Molecular Bioscience The University of Queensland St Lucia QLD Australia
| | - Glenn F. King
- Institute for Molecular Bioscience The University of Queensland St Lucia QLD Australia
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32
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Baswan SM, Klosner AE, Glynn K, Rajgopal A, Malik K, Yim S, Stern N. Therapeutic Potential of Cannabidiol (CBD) for Skin Health and Disorders. Clin Cosmet Investig Dermatol 2020; 13:927-942. [PMID: 33335413 PMCID: PMC7736837 DOI: 10.2147/ccid.s286411] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 11/15/2020] [Indexed: 12/17/2022]
Abstract
Though there is limited research confirming the purported topical benefits of cannabinoids, it is certain that cutaneous biology is modulated by the human endocannabinoid system (ECS). Receptors from the ECS have been identified in the skin and systemic abuse of synthetic cannabinoids, and their analogs, have also been associated with the manifestation of dermatological disorders, indicating the effects of the ECS on cutaneous biology. In particular, cannabidiol (CBD), a non-psychoactive compound from the cannabis plant, has garnered significant attention in recent years for its anecdotal therapeutic potential for various pathologies, including skin and cosmetic disorders. Though a body of preclinical evidence suggests topical application of CBD may be efficacious for some skin disorders, such as eczema, psoriasis, pruritis, and inflammatory conditions, confirmed clinical efficacy and elucidation of underlying molecular mechanisms have yet to be fully identified. This article provides an update on the advances in CBD research to date and the potential areas of future exploration.
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Affiliation(s)
- Sudhir M Baswan
- Innovation and Science, Amway Corporation, Ada, MI, 49355, USA
| | - Allison E Klosner
- Innovation and Science, Nutrilite Health Institute, Amway Corporation, Buena Park, CA, 90621, USA
| | - Kelly Glynn
- Innovation and Science, Amway Corporation, Ada, MI, 49355, USA
| | - Arun Rajgopal
- Innovation and Science, Amway Corporation, Ada, MI, 49355, USA
| | - Kausar Malik
- Innovation and Science, Amway Corporation, Ada, MI, 49355, USA
| | - Sunghan Yim
- Innovation and Science, Amway Corporation, Ada, MI, 49355, USA
| | - Nathan Stern
- Innovation and Science, Amway Corporation, Ada, MI, 49355, USA
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Liampas A, Rekatsina M, Vadalouca A, Paladini A, Varrassi G, Zis P. Pharmacological Management of Painful Peripheral Neuropathies: A Systematic Review. Pain Ther 2020; 10:55-68. [PMID: 33145709 PMCID: PMC8119529 DOI: 10.1007/s40122-020-00210-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 10/08/2020] [Indexed: 12/28/2022] Open
Abstract
Introduction Peripheral neuropathic pain (PNP) arises either acutely or in the chronic phase of a lesion or disease of the peripheral nervous system and is associated with a notable disease burden. The management of PNP is often challenging. The aim of this systematic review was to evaluate current evidence, derived from randomized controlled trials (RCTs) that have assessed pharmacological interventions for the treatment of PNP due to polyneuropathy (PN). Methods A systematic search of the PubMed database led to the identification of 538 papers, of which 457 were excluded due to not meeting the eligibility criteria, and two articles were identified through screening of the reference lists of the 81 eligible studies. Ultimately, 83 papers were included in this systematic review. Results The best available evidence for the management of painful diabetic polyneuropathy (DPN) is for amitriptyline, duloxetine, gabapentin, pregabalin and venlafaxine as monotherapies and oxycodone as add-on therapy (level II of evidence). Tramadol appears to be effective when used as a monotherapy and add-on therapy in patients with PN of various etiologies (level II of evidence). Weaker evidence (level III) is available on the effectiveness of several other agents discussed in this review for the management of PNP due to PN. Discussion Response to treatment may be affected by the underlying pathophysiological mechanisms that are involved in the pathogenesis of the PN and, therefore, it is very important to thoroughly investigate patients presenting with PNP to determine the causes of this neuropathy. Future RCTs should be conducted to shed more light on the use of pharmacological approaches in patients with other forms of PNP and to design specific treatment algorithms. Electronic supplementary material The online version of this article (10.1007/s40122-020-00210-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | | | - Athina Vadalouca
- Pain and Palliative Care Center, Athens Medical Center, Athens, Greece
| | - Antonella Paladini
- Department of Life, Health and Environmental Sciences (MESVA), University of L'Aquila, L'Aquila, Italy
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Wilkinson ID, Teh K, Heiberg-Gibbons F, Awadh M, Kelsall A, Shillo P, Sloan G, Tesfaye S, Selvarajah D. Determinants of Treatment Response in Painful Diabetic Peripheral Neuropathy: A Combined Deep Sensory Phenotyping and Multimodal Brain MRI Study. Diabetes 2020; 69:1804-1814. [PMID: 32471808 DOI: 10.2337/db20-0029] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 05/26/2020] [Indexed: 11/13/2022]
Abstract
Painful diabetic peripheral neuropathy (DPN) is difficult to manage, as treatment response is often varied. The primary aim of this study was to examine differences in pain phenotypes between responders and nonresponders to intravenous lidocaine treatment using quantitative sensory testing. The secondary aim was to explore differences in brain structure and functional connectivity with treatment response. Forty-five consecutive patients who received intravenous lidocaine treatment for painful DPN were screened. Twenty-nine patients who met the eligibility criteria (responders, n = 14, and nonresponders, n = 15) and 26 healthy control subjects underwent detailed sensory profiling. Subjects also underwent multimodal brain MRI. A greater proportion of patients with the irritable (IR) nociceptor phenotype were responders to intravenous lidocaine treatment compared with nonresponders. The odds ratio of responding to intravenous lidocaine was 8.67 times greater (95% CI 1.4-53.8) for the IR nociceptor phenotype. Responders to intravenous lidocaine also had significantly greater mean primary somatosensory cortex cortical volume and functional connectivity between the insula cortex and the corticolimbic circuitry. This study provides preliminary evidence for a mechanism-based approach for individualizing therapy in patients with painful DPN.
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Affiliation(s)
- Iain David Wilkinson
- Academic Department of Radiology, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, U.K
| | - Kevin Teh
- Academic Department of Radiology, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, U.K
| | | | - Mohammad Awadh
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, U.K
| | - Alan Kelsall
- Diabetes Research Department, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, U.K
| | - Pallai Shillo
- Diabetes Research Department, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, U.K
| | - Gordon Sloan
- Diabetes Research Department, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, U.K
| | - Solomon Tesfaye
- Diabetes Research Department, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, U.K
| | - Dinesh Selvarajah
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, U.K.
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Davis KD, Aghaeepour N, Ahn AH, Angst MS, Borsook D, Brenton A, Burczynski ME, Crean C, Edwards R, Gaudilliere B, Hergenroeder GW, Iadarola MJ, Iyengar S, Jiang Y, Kong JT, Mackey S, Saab CY, Sang CN, Scholz J, Segerdahl M, Tracey I, Veasley C, Wang J, Wager TD, Wasan AD, Pelleymounter MA. Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities. Nat Rev Neurol 2020; 16:381-400. [PMID: 32541893 PMCID: PMC7326705 DOI: 10.1038/s41582-020-0362-2] [Citation(s) in RCA: 245] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2020] [Indexed: 02/06/2023]
Abstract
Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.
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Affiliation(s)
- Karen D Davis
- Department of Surgery and Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
- Division of Brain, Imaging and Behaviour, Krembil Brain Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.
| | - Nima Aghaeepour
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Martin S Angst
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - David Borsook
- Center for Pain and the Brain, Harvard Medical School, Boston, MA, USA
| | | | | | | | - Robert Edwards
- Pain Management Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Brice Gaudilliere
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Georgene W Hergenroeder
- The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Michael J Iadarola
- Department of Perioperative Medicine, Clinical Center, NIH, Rockville, MD, USA
| | - Smriti Iyengar
- Division of Translational Research, National Institute of Neurological Disorders and Stroke, NIH, Rockville, MD, USA
| | - Yunyun Jiang
- The Biostatistics Center, Milken Institute School of Public Health, The George Washington University, Washington, DC, USA
| | - Jiang-Ti Kong
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Sean Mackey
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Carl Y Saab
- Department of Neuroscience and Department of Neurosurgery, Carney Institute for Brain Science, Brown University, Providence, RI, USA
| | - Christine N Sang
- Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Joachim Scholz
- Neurocognitive Disorders, Pain and New Indications, Biogen, Cambridge, MA, USA
| | | | - Irene Tracey
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | | | - Jing Wang
- Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU School of Medicine, New York, NY, USA
| | - Tor D Wager
- Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, USA
| | - Ajay D Wasan
- Anesthesiology and Perioperative Medicine and Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mary Ann Pelleymounter
- Division of Translational Research, National Institute of Neurological Disorders and Stroke, NIH, Rockville, MD, USA
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McPherson T, Fontane P, Bilger R. Patient Experiences with Compounded Topical Pain Creams. J Pain Palliat Care Pharmacother 2020; 34:82-89. [DOI: 10.1080/15360288.2020.1733168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Rosenberger DC, Blechschmidt V, Timmerman H, Wolff A, Treede RD. Challenges of neuropathic pain: focus on diabetic neuropathy. J Neural Transm (Vienna) 2020; 127:589-624. [PMID: 32036431 PMCID: PMC7148276 DOI: 10.1007/s00702-020-02145-7] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 01/19/2020] [Indexed: 02/07/2023]
Abstract
Neuropathic pain is a frequent condition caused by a lesion or disease of the central or peripheral somatosensory nervous system. A frequent cause of peripheral neuropathic pain is diabetic neuropathy. Its complex pathophysiology is not yet fully elucidated, which contributes to underassessment and undertreatment. A mechanism-based treatment of painful diabetic neuropathy is challenging but phenotype-based stratification might be a way to develop individualized therapeutic concepts. Our goal is to review current knowledge of the pathophysiology of peripheral neuropathic pain, particularly painful diabetic neuropathy. We discuss state-of-the-art clinical assessment, validity of diagnostic and screening tools, and recommendations for the management of diabetic neuropathic pain including approaches towards personalized pain management. We also propose a research agenda for translational research including patient stratification for clinical trials and improved preclinical models in relation to current knowledge of underlying mechanisms.
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Affiliation(s)
- Daniela C Rosenberger
- Department of Neurophysiology, Mannheim Center for Translational Neuroscience (MCTN), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Vivian Blechschmidt
- Department of Neurophysiology, Mannheim Center for Translational Neuroscience (MCTN), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Hans Timmerman
- Department of Anesthesiology, Pain Center, University Medical Center of Groningen (UMCG), University of Groningen, Groningen, The Netherlands
| | - André Wolff
- Department of Anesthesiology, Pain Center, University Medical Center of Groningen (UMCG), University of Groningen, Groningen, The Netherlands
| | - Rolf-Detlef Treede
- Department of Neurophysiology, Mannheim Center for Translational Neuroscience (MCTN), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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Alam U, Sloan G, Tesfaye S. Treating Pain in Diabetic Neuropathy: Current and Developmental Drugs. Drugs 2020; 80:363-384. [DOI: 10.1007/s40265-020-01259-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Raouf M, Bettinger J, Wegrzyn EW, Mathew RO, Fudin JJ. Pharmacotherapeutic Management of Neuropathic Pain in End-Stage Renal Disease. KIDNEY DISEASES 2020; 6:157-167. [PMID: 32523958 DOI: 10.1159/000504299] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 10/09/2019] [Indexed: 12/25/2022]
Abstract
Background Chronic noncancer pain is pervasive throughout the general patient population, transcending all chronic disease states. Patients with end-stage renal disease (ESRD) present a complicated population for which medication management requires careful consideration of the pathogenesis of ESRD and intimate knowledge of pharmacology. The origin of pain must also guide treatment options. As such, the presentation of neuropathic pain in ESRD can present a challenging case. The authors aim to provide a review of available classes of medications and considerations for the treatment of neuropathic pain in ESRD. Summary In this narrative review, the authors discuss important strategies and considerations for the treatment of neuropathic pain in ESRD, including the pathogenesis of neuropathic pain, physiological changes for consideration in ESRD patients, and disease-specific consideration for medication selection. Pharmacotherapeutic classes discussed include: anticonvulsants, antiarrhythmics, antidepressants, topicals, and opioids. Key Message Pain management in ESRD patients requires careful assessment of drug-specific properties, accumulation, metabolism (presence of active/toxic metabolites), extraction by dialysis, and presence of drug - drug interactions. In the absence of pharmacokinetic data in ESRD patients, therapeutic window and potential risks should be factored in the decision making along with continued monitoring throughout therapy.
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Affiliation(s)
- Mena Raouf
- Department of Pain Management, Kaiser Permanente, Federal Way, Washington, USA
| | - Jeffrey Bettinger
- Department of Pain Management, Saratoga Hospital Medical Group, Saratoga, New York, USA
| | - Erica W Wegrzyn
- Department of Pain Management, Stratton VA Medical Center, Albany, New York, USA
| | - Roy O Mathew
- Department of Nephrology, William Jennings Bryan Dorn VA Medical Center, Columbia, South Carolina, USA
| | - Jeffrey J Fudin
- Department of Pain Management, Stratton VA Medical Center, Albany, New York, USA
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Ardeleanu V, Toma A, Pafili K, Papanas N, Motofei I, Diaconu CC, Rizzo M, Pantea Stoian A. Current Pharmacological Treatment of Painful Diabetic Neuropathy: A Narrative Review. ACTA ACUST UNITED AC 2020; 56:medicina56010025. [PMID: 31936646 PMCID: PMC7022869 DOI: 10.3390/medicina56010025] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 01/03/2020] [Accepted: 01/06/2020] [Indexed: 02/07/2023]
Abstract
Background and Objectives: Distal symmetrical polyneuropathy (DSPN) is one of the most common chronic complications of diabetes mellitus. Although it is usually characterized by progressive sensory loss, some patients may develop chronic pain. Assessment of DSPN is not difficult, but the biggest challenge is making the correct diagnosis and choosing the right treatment. The treatment of DSPN has three primary objectives: glycemic control, pathogenic mechanisms, and pain management. The aim of this brief narrative review is to summarize the current pharmacological treatment of painful DSPN. It also summarizes knowledge on pathogenesis-oriented therapy, which is generally overlooked in many publications and guidelines. Materials and Methods: The present review reports the relevant information available on DSPN treatment. The search was performed on PubMed, Cochrane, Semantic Scholar, Medline, Scopus, and Cochrane Library databases, including among others the terms "distal symmetrical polyneuropathy", "neuropathic pain treatment", "diabetic neuropathy", "diabetes complications", "glycaemic control", "antidepressants", "opioids", and "anticonvulsants". Results: First-line drugs include antidepressants (selective serotonin reuptake inhibitors and tricyclic antidepressants) and pregabalin. Second- and third-line drugs include opioids and topical analgesics. While potentially effective in the treatment of neuropathic pain, opioids are not considered to be the first choice because of adverse reactions and addiction concerns. Conclusions: DSPN is a common complication in patients with diabetes, and severely affects the quality of life of these patients. Although multiple therapies are available, the guidelines and recommendations regarding the treatment of diabetic neuropathy have failed to offer a unitary consensus, which often hinders the therapeutic options in clinical practice.
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Affiliation(s)
- Valeriu Ardeleanu
- Department of Surgery, University “Dunarea de Jos”, 800008 Galati, Romania;
- Department of Surgery, University “Ovidius’’, 900470 Constanta, Romania
- Arestetic Clinic, 800098 Galati, Romania
| | - Alexandra Toma
- Department of Surgery, University “Dunarea de Jos”, 800008 Galati, Romania;
- Department of Surgery, Emergency County Clinical Hospital “Sf. Apostol Andrei”, 800578 Galati, Romania
- Correspondence: (A.T.); (A.P.S.)
| | - Kalliopi Pafili
- Second Department of Internal Medicine, Diabetes Centre-Diabetic Foot Clinic, Democritus University of Thrace, University Hospital of Alexandroupolis, 681 00 Alexandroupolis, Greece; (K.P.); (N.P.)
| | - Nikolaos Papanas
- Second Department of Internal Medicine, Diabetes Centre-Diabetic Foot Clinic, Democritus University of Thrace, University Hospital of Alexandroupolis, 681 00 Alexandroupolis, Greece; (K.P.); (N.P.)
| | - Ion Motofei
- Department of Surgery, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Camelia Cristina Diaconu
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Manfredi Rizzo
- Biomedical Department of Internal Medicine and Medical Specialties School of Medicine, University of Palermo, 90133 Palermo, Italy;
- Division of Endocrinology, Diabetes and Metabolism, University of South Carolina School of Medicine Columbia, Columbia, SC 29209, USA
| | - Anca Pantea Stoian
- Diabetes, Nutrition and Metabolic Diseases Department, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Correspondence: (A.T.); (A.P.S.)
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Sanna MD, Borgonetti V, Masini E, Galeotti N. Histamine H 4 receptor stimulation in the locus coeruleus attenuates neuropathic pain by promoting the coeruleospinal noradrenergic inhibitory pathway. Eur J Pharmacol 2019; 868:172859. [PMID: 31843515 DOI: 10.1016/j.ejphar.2019.172859] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 11/18/2019] [Accepted: 12/10/2019] [Indexed: 11/24/2022]
Abstract
The locus coeruleus (LC) adrenergic nuclei constitute a pain-control inhibitory system nucleus implicated in descending modulation of pain through the action on spinal α2-adrenoceptors. Histaminergic innervation from the tuberomammillary nucleus of the LC increases firing of noradrenergic neurons and might contribute to pain control. Here we evaluated the contribution of LC histaminergic innervation in descending modulation of neuropathic hypersensitivity, by investigating the role of the histamine H4 receptor subtype in a mouse model of neuropathic pain. Intra LC administration of the H4 agonist VUF 8430 attenuated mechanical and thermal allodynia of mice that underwent spared nerve injury (SNI). Similarly, histamine in the LC showed mechanical and thermal anti-hypersensitivity. Pretreatment of LC with JNJ 10191584 (H4 antagonist) prevented the beneficial effect of VUF 8430 and histamine on nociceptive behaviour. Comparable results were obtained after intrathecal administration of drugs. The intrathecal administration of the α2-adrenoceptor agonist clonidine ameliorated mechanical and thermal allodynia in SNI mice. The clonidine-induced anti-hypersensitivity effect was prevented by intra LC pretreatment with JNJ 10191584. In addition, clonidine failed to suppress neuropathic pain in H4 deficient mice. LC H4 receptors showed a ubiquitous distribution within LC, a neuronal localization and H4 immunostaining was detected on noradrenergic neurons expressing phosphorylated cAMP response element-binding protein (CREB), a marker of neuronal activation. Under pain pathological conditions H4 stimulation might promote the activation of the coeruleospinal noradrenergic neurons that exert an inhibitory control over spinal dorsal horn neuronal excitability. Thus, histamine H4 receptor stimulation may represent a perspective for neuropathic pain management.
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Affiliation(s)
- Maria Domenica Sanna
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, Viale G. Pieraccini 6, University of Florence, 50139, Florence, Italy
| | - Vittoria Borgonetti
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, Viale G. Pieraccini 6, University of Florence, 50139, Florence, Italy
| | - Emanuela Masini
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, Viale G. Pieraccini 6, University of Florence, 50139, Florence, Italy
| | - Nicoletta Galeotti
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, Viale G. Pieraccini 6, University of Florence, 50139, Florence, Italy.
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Hincker A, Frey K, Rao L, Wagner-Johnston N, Ben Abdallah A, Tan B, Amin M, Wildes T, Shah R, Karlsson P, Bakos K, Kosicka K, Kagan L, Haroutounian S. Somatosensory predictors of response to pregabalin in painful chemotherapy-induced peripheral neuropathy: a randomized, placebo-controlled, crossover study. Pain 2019; 160:1835-1846. [PMID: 31335651 PMCID: PMC6687437 DOI: 10.1097/j.pain.0000000000001577] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 02/25/2019] [Accepted: 03/29/2019] [Indexed: 01/22/2023]
Abstract
Painful chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and treatment-resistant sequela of many chemotherapeutic medications. Ligands of α2δ subunits of voltage-gated Ca channels, such as pregabalin, have shown efficacy in reducing mechanical sensitivity in animal models of neuropathic pain. In addition, some data suggest that pregabalin may be more efficacious in relieving neuropathic pain in subjects with increased sensitivity to pinprick. We hypothesized that greater mechanical sensitivity, as quantified by decreased mechanical pain threshold at the feet, would be predictive of a greater reduction in average daily pain in response to pregabalin vs placebo. In a prospective, randomized, double-blinded study, 26 patients with painful CIPN from oxaliplatin, docetaxel, or paclitaxel received 28-day treatment with pregabalin (titrated to maximum dose 600 mg per day) and placebo in crossover design. Twenty-three participants were eligible for efficacy analysis. Mechanical pain threshold was not significantly correlated with reduction in average pain (P = 0.97) or worst pain (P = 0.60) in response to pregabalin. There was no significant difference between pregabalin and placebo in reducing average daily pain (22.5% vs 10.7%, P = 0.23) or worst pain (29.2% vs 16.0%, P = 0.13) from baseline. Post hoc analysis of patients with CIPN caused by oxaliplatin (n = 18) demonstrated a larger reduction in worst pain with pregabalin than with placebo (35.4% vs 14.6%, P = 0.04). In summary, baseline mechanical pain threshold tested on dorsal feet did not meaningfully predict the analgesic response to pregabalin in painful CIPN.
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Affiliation(s)
- Alexander Hincker
- Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, United States
- Washington University Pain Center, Washington University School of Medicine, St Louis, MO, United States
| | - Karen Frey
- Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, United States
| | - Lesley Rao
- Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, United States
- Washington University Pain Center, Washington University School of Medicine, St Louis, MO, United States
| | - Nina Wagner-Johnston
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Arbi Ben Abdallah
- Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, United States
| | - Benjamin Tan
- Department of Medicine, Washington University School of Medicine, St Louis, MO, United States
| | - Manik Amin
- Department of Medicine, Washington University School of Medicine, St Louis, MO, United States
| | - Tanya Wildes
- Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, United States
- Department of Medicine, Washington University School of Medicine, St Louis, MO, United States
| | - Rajiv Shah
- Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, United States
- Washington University Pain Center, Washington University School of Medicine, St Louis, MO, United States
| | - Pall Karlsson
- Department of Clinical Medicine, Danish Pain Research Center, Aarhus University, Aarhus, Denmark
- Section for Stereology and Microscopy, Core Centre for Molecular Morphology, Aarhus University, Aarhus, Denmark
| | - Kristopher Bakos
- Investigation Drug Service, Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, MO, United States
| | - Katarzyna Kosicka
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan, Poland
| | - Leonid Kagan
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, United States
| | - Simon Haroutounian
- Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, United States
- Washington University Pain Center, Washington University School of Medicine, St Louis, MO, United States
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Bates D, Schultheis BC, Hanes MC, Jolly SM, Chakravarthy KV, Deer TR, Levy RM, Hunter CW. A Comprehensive Algorithm for Management of Neuropathic Pain. PAIN MEDICINE (MALDEN, MASS.) 2019; 20:S2-S12. [PMID: 31152178 PMCID: PMC6544553 DOI: 10.1093/pm/pnz075] [Citation(s) in RCA: 213] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The objective of this review was to merge current treatment guidelines and best practice recommendations for management of neuropathic pain into a comprehensive algorithm for primary physicians. The algorithm covers assessment, multidisciplinary conservative care, nonopioid pharmacological management, interventional therapies, neurostimulation, low-dose opioid treatment, and targeted drug delivery therapy. METHODS Available literature was identified through a search of the US National Library of Medicine's Medline database, PubMed.gov. References from identified published articles also were reviewed for relevant citations. RESULTS The algorithm provides a comprehensive treatment pathway from assessment to the provision of first- through sixth-line therapies for primary care physicians. Clear indicators for progression of therapy from firstline to sixth-line are provided. Multidisciplinary conservative care and nonopioid medications (tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, gabapentanoids, topicals, and transdermal substances) are recommended as firstline therapy; combination therapy (firstline medications) and tramadol and tapentadol are recommended as secondline; serotonin-specific reuptake inhibitors/anticonvulsants/NMDA antagonists and interventional therapies as third-line; neurostimulation as a fourth-line treatment; low-dose opioids (no greater than 90 morphine equivalent units) are fifth-line; and finally, targeted drug delivery is the last-line therapy for patients with refractory pain. CONCLUSIONS The presented treatment algorithm provides clear-cut tools for the assessment and treatment of neuropathic pain based on international guidelines, published data, and best practice recommendations. It defines the benefits and limitations of the current treatments at our disposal. Additionally, it provides an easy-to-follow visual guide of the recommended steps in the algorithm for primary care and family practitioners to utilize.
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Affiliation(s)
| | - B Carsten Schultheis
- Muskuloskelettales Zentrum - Interventionelle Schmerztherapie, Krankenhaus Neuwerk “Maria von den Aposteln,” Mönchengladbach, Germany
| | | | - Suneil M Jolly
- Louisiana Pain Specialists, New Orleans, Louisiana
- New Orleans East Hospital, New Orleans, Louisiana
| | - Krishnan V Chakravarthy
- Department of Anesthesiology and Pain Medicine, University of California San Diego Health Sciences, La Jolla, California
- Veterans Administration San Diego Healthcare System, San Diego, California
| | - Timothy R Deer
- The Spine and Nerve Center of the Virginias, Charleston, West Virginia
| | | | - Corey W Hunter
- Ainsworth Institute of Pain Management, New York, New York, USA
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Designing and conducting proof-of-concept chronic pain analgesic clinical trials. Pain Rep 2019; 4:e697. [PMID: 31583338 PMCID: PMC6749910 DOI: 10.1097/pr9.0000000000000697] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 09/24/2018] [Accepted: 09/26/2018] [Indexed: 02/07/2023] Open
Abstract
Introduction: The evolution of pain treatment is dependent on successful development and testing of interventions. Proof-of-concept (POC) studies bridge the gap between identification of a novel target and evaluation of the candidate intervention's efficacy within a pain model or the intended clinical pain population. Methods: This narrative review describes and evaluates clinical trial phases, specific POC pain trials, and approaches to patient profiling. Results: We describe common POC trial designs and their value and challenges, a mechanism-based approach, and statistical issues for consideration. Conclusion: Proof-of-concept trials provide initial evidence for target use in a specific population, the most appropriate dosing strategy, and duration of treatment. A significant goal in designing an informative and efficient POC study is to ensure that the study is safe and sufficiently sensitive to detect a preliminary efficacy signal (ie, a potentially valuable therapy). Proof-of-concept studies help avoid resources wasted on targets/molecules that are not likely to succeed. As such, the design of a successful POC trial requires careful consideration of the research objective, patient population, the particular intervention, and outcome(s) of interest. These trials provide the basis for future, larger-scale studies confirming efficacy, tolerability, side effects, and other associated risks.
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Yang XD, Fang PF, Xiang DX, Yang YY. Topical treatments for diabetic neuropathic pain. Exp Ther Med 2019; 17:1963-1976. [PMID: 30783472 PMCID: PMC6364237 DOI: 10.3892/etm.2019.7173] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 11/22/2018] [Indexed: 12/14/2022] Open
Abstract
Diabetic neuropathic pain (DNP) has a huge impact on quality of life and can be difficult to treat. Oral treatment is the most frequently used method for DNP, but its use is often limited by systemic side effects. Topical use of drugs as an alternative option for DNP treatment is currently gaining interest. In the present review, a summary is provided of the available agents for topical use in patients with DNP, including lidocaine plasters or patches, capsaicin cream, gel or patches, amitriptyline cream, clonidine gel, ketamine cream, extracts from medicinal plants including nutmeg extracts and Citrullus colocynthis extract oil, and certain compounded topical analgesics. Furthermore, the potential efficacy of these treatments is addressed according to the available clinical research literature. It has been indicated that these topical drugs have the potential to be valuable additional options for the management of DNP, with adequate safety and continuous long-term treatment efficacy. Compounded topical agents are also effective and safe for patients with DNP and could be another area worthy of further investigation based on the strategy of using low-dose, complementary therapies for DNP. The findings indicate that developing topical drugs acting on different targets in the process of DNP is a valuable area of future research.
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Affiliation(s)
- Xi-Ding Yang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China.,Phase I Clinical Trial Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Ping-Fei Fang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China.,Phase I Clinical Trial Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Da-Xiong Xiang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China.,Hunan Provincial Engineering Research Center of Translational Medical and Innovative Drug, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Yong-Yu Yang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China.,Hunan Provincial Engineering Research Center of Translational Medical and Innovative Drug, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
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Vilar S, Castillo JM, Munuera Martínez PV, Reina M, Pabón M. Therapeutic alternatives in painful diabetic neuropathy: a meta-analysis of randomized controlled trials. Korean J Pain 2018; 31:253-260. [PMID: 30310550 PMCID: PMC6177536 DOI: 10.3344/kjp.2018.31.4.253] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 06/22/2018] [Accepted: 06/22/2018] [Indexed: 12/22/2022] Open
Abstract
Background One of the most frequent problems caused by diabetes is the so called painful diabetic neuropathy. This condition can be treated through numerous types of therapy. The purpose of this study was to analyze, as a meta-analysis, different treatments used to alleviate painful diabetic neuropathy, with the aim of generating results that help making decisions when applying such treatments to tackle this pathology. Methods A search was conducted in the main databases for Health Sciences, such as PUBMED, Web of Science (WOS), and IME biomedicina (Spanish Medical Reports in Biomedicine), to gather randomized controlled trials about treatments used for painful diabetic neuropathy. The analyzed studies were required to meet the inclusion criteria selected, especially those results related to pain intensity. Results Nine randomized controlled trials were chosen. The meta-analysis shows significant positive effects for those treatments based on tapentadol [g: -1.333, 95% CI (-1.594; -1.072), P < 0.05], duloxetine [g: -1.622, 95 % CI (-1.650; -1.594), P < 0.05], pregabalin [g: -0.607, 95% CI (-0.980; -0.325), P < 0.05], and clonidine [g: -0.242, 95 % CI (-0.543; -0.058), P < 0.05]. Conclusions This meta-analysis indicates the effectiveness of the treatments based on duloxetine, gabapentin and pregabalin, as well as other drugs, such as tapentadol and topic clonidine, whose use is better prescribed in more specific situations. The results provided can help increase the knowledge about the treatment of painful diabetic neuropathy and also in the making of clinical practice guidelines for healthcare professionals.
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Affiliation(s)
- Samuel Vilar
- Pain Clinic, University Hospital Virgen del Rocío, Seville, Spain
| | - Jose Manuel Castillo
- Department of Nursing, Physiotherapy and Podiatry, University of Seville, Seville, Spain
| | | | - María Reina
- Department of Nursing, Physiotherapy and Podiatry, University of Seville, Seville, Spain
| | - Manuel Pabón
- Department of Nursing, Physiotherapy and Podiatry, University Hospital Cruz Roja, Seville, Spain
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Structural, functional, and symptom relations in painful distal symmetric polyneuropathies: a systematic review. Pain 2018; 160:286-297. [DOI: 10.1097/j.pain.0000000000001381] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Fitzmaurice BC, Rayen ATA. Treatments for neuropathic pain: up-to-date evidence and recommendations. BJA Educ 2018; 18:277-283. [PMID: 33456845 DOI: 10.1016/j.bjae.2018.06.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2018] [Indexed: 01/25/2023] Open
Affiliation(s)
| | - A T A Rayen
- Sandwell and West Birmingham NHS Trust, Birmingham, UK
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