|
1
|
Allgood JE, Whitney L, Goodwin J, Chong BSH, Brooks A, Pullan J. The Role of Pain Medications in Modulating Peripheral Nerve Injury Recovery. J Clin Pharmacol 2025; 65:411-423. [PMID: 39492597 DOI: 10.1002/jcph.6156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 10/15/2024] [Indexed: 11/05/2024]
Abstract
Peripheral nerve injuries (PNIs) are common, costly, and cause significant pain. Effective management of PNIs involves tailoring medications to the injury type as well as understanding the pharmacokinetics/pharmacodynamics to support nerve regeneration and reduce pain. Opioids act on opioid receptors to significantly reduce pain for many patients, but there are significant addiction risks and side effects. In addition, opioids may exacerbate pain sensitivity and affect nerve regeneration. Non-steroidal anti-inflammatory drugs or acetaminophen act on cyclooxygenase enzymes and are commonly used for nerve pain, with 34.7% of people using them for neuropathic pain. While effective for mild pain, they are often combined with opioids, gamma-aminobutyric acid (GABA) analogs, lidocaine, or corticosteroids for more severe pain. Corticosteroids, mimicking adrenal hormones like cortisol, treat PNI-related inflammation and pain. Their pharmacokinetics are complex, often requiring local injections in order to minimize systemic risks while effectively treating PNIs. Lidocaine, a common local anesthetic, blocks ion channels in the central nervous system (CNS) and peripheral nerves, providing strong analgesic and anti-inflammatory effects. If used improperly, lidocaine can cause neuronal toxicity instead of anesthetic effect. GABA acts as an inhibitory neurotransmitter in the CNS and its drug analogs like pregabalin and gabapentin can alleviate neuropathic pain by binding to voltage-gated Ca2+ channels, inhibiting neurotransmitter release. These pain medications are commonly prescribed for PNIs despite a limited guidance on their effects on nerve regeneration. This review will discuss these drug's mechanisms of action, pharmacokinetics/pharmacodynamics, and their clinical application to highlight their effect on the PNI recovery.
Collapse
Affiliation(s)
- JuliAnne E Allgood
- Department of Neuroscience, University of Wyoming, Laramie, WY, USA
- Co-first authorship, Ivins, UT, USA
| | - Logan Whitney
- Department of Chemistry and Physics, Southern Utah University, Cedar City, UT, USA
- Co-first authorship, Ivins, UT, USA
| | - Jeffrey Goodwin
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT, USA
| | - Brian S H Chong
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT, USA
| | - Amanda Brooks
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT, USA
| | - Jessica Pullan
- Department of Chemistry and Physics, Southern Utah University, Cedar City, UT, USA
| |
Collapse
|
|
2
|
Shah KB, Rana DA, Mehta YD, Malhotra SD. Comparative efficacy and safety of gabapentin, pregabalin, oxcarbazepine, and duloxetine in diabetic peripheral neuropathy: A network meta-analysis. Perspect Clin Res 2024; 15:202-208. [PMID: 39583921 PMCID: PMC11584157 DOI: 10.4103/picr.picr_218_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 12/14/2023] [Accepted: 12/27/2023] [Indexed: 11/26/2024] Open
Abstract
Purpose To conduct a network meta-analysis comparing the safety and efficacy of gabapentin (GBP), pregabalin (PGB), oxcarbazepine (OXC), and duloxetine (DLX) in treating diabetic peripheral neuropathy (DPN). Materials and Methods The study's eligibility criteria includee randomized controlled trials (RCTs) with a focus on DPN patients receiving GBP, PGB, DLX, or OXC versus placebo. Noncompliant trials with incomplete information and observational studies were excluded. Results Twelve (RCTs) of PGB, 2 of GBP, 3 of DLX, and 1 of OXC met the inclusion criteria. When drugs were compared for efficacy (direct comparison), GBP (Odd's ratio [OR] = 3.208, P < 0.001) was most effective followed by OXC (OR = 2.4, P = 0.0248), DLX (OR = 2.346, P < 0.001), and PGB (OR = 2.161, P < 0.001). When drugs were compared for withdrawal due to adverse drug reaction (ADR) (direct comparison), GBP (OR = 1.3818, P = 0.766) was safest followed by PGB (OR = 2.16, P < 0.001), DLX (OR = 2.469, P < 0.001), and OXC (OR = 4.4967, P = 0.001). Indirect comparison was done for efficacy, DLX was statistically significant than PGB and OXC (DLX vs. PGB, P = 0.03; DLX vs. OXC, P = 0.02). When indirect comparison was done for patient withdrawal due to ADR, OXC was worst (GBP vs. OXC, P = 0.0001; PGB vs. OXC, P = 0.007; DLX vs. OXC, P = 0.015). When drugs were compared for individual ADRs (direct comparison), dizziness was most commonly seen with OXC (OR = 9.6535, P = 1.8425), headache with OXC (OR = 3.8686, P = 0.006), somnolence with PGB (OR = 5.189, P < 0.001), and nausea with DLX (OR = 3.264, P < 0.001). GBP was most effective and safest drug followed by OXC > DLX > PGB for efficacy and PGB > DLX > OXC for safety. Conclusion In evaluating medications for DPN against placebo, GBP and OXC demonstrated the highest effectiveness while maintaining a favorable safety profile.
Collapse
Affiliation(s)
| | - Devang A. Rana
- Department of Pharmacology, Smt.NHL MMC, Ahmedabad, Gujarat, India
| | | | | |
Collapse
|
|
3
|
Didangelos T, Karlafti E, Kotzakioulafi E, Giannoulaki P, Kontoninas Z, Kontana A, Evripidou P, Savopoulos C, Birkenfeld AL, Kantartzis K. Efficacy and Safety of the Combination of Palmitoylethanolamide, Superoxide Dismutase, Alpha Lipoic Acid, Vitamins B12, B1, B6, E, Mg, Zn and Nicotinamide for 6 Months in People with Diabetic Neuropathy. Nutrients 2024; 16:3045. [PMID: 39339645 PMCID: PMC11434759 DOI: 10.3390/nu16183045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 09/01/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
AIM To investigate the efficacy of Palmitoylethanolamide (PEA, 300 mg), Superoxide Dismutase (SOD, 70 UI), Alpha Lipoic Acid (ALA, 300 mg), vitamins B6 (1.5 mg), B1 (1.1 mg), B12 (2.5 mcg), E (7.5 mg), nicotinamide (9 mg), and minerals (Mg 30 mg, Zn 2.5 mg) in one tablet in people with Diabetic Neuropathy (DN). PATIENTS-METHODS In the present pilot study, 73 people (age 63.0 ± 9.9 years, 37 women) with type 2 Diabetes Mellitus (DMT2) (duration 17.5 ± 7.3 years) and DN were randomly assigned to receive either the combination of ten elements (2 tablets/24 h) in the active group (n = 36) or the placebo (n = 37) for 6 months. We used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE), measured vibration perception threshold (VPT) with biothesiometer, and Cardiovascular Autonomic Reflex Tests (CARTs). Nerve function was assessed by DPN Check [sural nerve conduction velocity (SNCV) and amplitude (SNAP)]. Sudomotor function was assessed with SUDOSCAN, which measures electrochemical skin conductance in hands and feet (ESCH and ESCF). Pain score (PS) was assessed with Pain DETECT questionnaire. Quality of life was assessed by questionnaire. RESULTS In the active group, there was a large improvement of pain (PS from 20.9 to 13.9, p < 0.001). There was also a significant improvement of vitamin B12 (B12) levels, MNSIQ, SNCV, VPT, and ESCF (222.1 vs. 576.3 pg/ mL, p < 0.001; 6.1 vs. 5.9, p = 0.017; 28.8 vs. 30.4, p = 0.001; 32.1 vs. 26.7, p = 0.001; and 72.2 vs. 74.8, p < 0.001 respectively). In the placebo group, neither pain (21.6 vs. 21.7, p = 0.870) or any other aforementioned parameters changed significantly, and MNSIE worsened (2.9 vs. 3.4, p < 0.001). As a result, changes from baseline to follow-up in pain, B12 levels, VPT, and MNSIQ differed significantly between the two groups (p < 0.001, 0.025, 0.009, and <0.001, respectively). CARTs, SNAP, ESCH did not significantly change in either of the two groups. CONCLUSIONS The combination of the ten elements in one tablet for 6 months at a daily dose of two tablets in people with DN significantly improves pain, vibration perception threshold, and B12 levels.
Collapse
Affiliation(s)
- Triantafyllos Didangelos
- Diabetes Center, 1st Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece; (E.K.); (E.K.); (Z.K.); (A.K.); (P.E.); (C.S.)
| | - Eleni Karlafti
- Diabetes Center, 1st Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece; (E.K.); (E.K.); (Z.K.); (A.K.); (P.E.); (C.S.)
| | - Evangelia Kotzakioulafi
- Diabetes Center, 1st Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece; (E.K.); (E.K.); (Z.K.); (A.K.); (P.E.); (C.S.)
| | - Parthena Giannoulaki
- Department of Clinical Nutrition and Dietetics, AHEPA Hospital, 54636 Thessaloniki, Greece;
| | - Zisis Kontoninas
- Diabetes Center, 1st Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece; (E.K.); (E.K.); (Z.K.); (A.K.); (P.E.); (C.S.)
| | - Anastasia Kontana
- Diabetes Center, 1st Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece; (E.K.); (E.K.); (Z.K.); (A.K.); (P.E.); (C.S.)
| | - Polykarpos Evripidou
- Diabetes Center, 1st Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece; (E.K.); (E.K.); (Z.K.); (A.K.); (P.E.); (C.S.)
| | - Christos Savopoulos
- Diabetes Center, 1st Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece; (E.K.); (E.K.); (Z.K.); (A.K.); (P.E.); (C.S.)
| | - Andreas L. Birkenfeld
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University of Tübingen, 72076 Tübingen, Germany; (A.L.B.); (K.K.)
- Institute for Diabetes Research and Metabolic Diseases (IDM), Helmholtz Centre Munich, University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany
| | - Konstantinos Kantartzis
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University of Tübingen, 72076 Tübingen, Germany; (A.L.B.); (K.K.)
- Institute for Diabetes Research and Metabolic Diseases (IDM), Helmholtz Centre Munich, University of Tübingen, 72076 Tübingen, Germany
- German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany
| |
Collapse
|
|
4
|
Borghare PT, Methwani DA, Tidke M, Nasre Y, Kumar T. Non-invasive Management of Head and Neck Neuralgia: A Literature Review. Cureus 2024; 16:e66906. [PMID: 39280461 PMCID: PMC11399694 DOI: 10.7759/cureus.66906] [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: 07/30/2024] [Accepted: 08/11/2024] [Indexed: 09/18/2024] Open
Abstract
Head and neck neuralgia is a prevalent condition impacting millions worldwide, necessitating both invasive and non-invasive management strategies. This review focuses specifically on non-invasive approaches. Using the International Classification of Headache Disorders (ICHD-3), we categorized neuralgia causing head and neck pain to structure our literature search. Our review identified several non-invasive management techniques, including physiotherapy, pharmacological treatments, Pulsed Radiofrequency, local anesthesia blocks, Botulinum toxin injections, and non-invasive neuromodulation. This review highlights various effective non-invasive strategies for managing head and neck neuralgias, supported by studies published until 2023. These findings emphasize the clinical relevance of tailoring treatment plans to individual patient needs, considering the specific type of neuralgia and optimizing outcomes in clinical practice.
Collapse
Affiliation(s)
- Pramod T Borghare
- Otolaryngology, Mahatma Gandhi Ayurved College Hospital and Research, Wardha, IND
| | - Disha A Methwani
- Otolaryngology, NKP Salve Institute Of Medical Sciences & Research Centre And Lata Mangeshkar Hospital, Nagpur, IND
| | - Megha Tidke
- Otolaryngology, Mahatma Gandhi Ayurved College Hospital and Research, Wardha, IND
| | | | - Tanish Kumar
- Medicine, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| |
Collapse
|
|
5
|
Bouhassira D, Tesfaye S, Sarkar A, Soisalon-Soininen S, Stemper B, Baron R. Efficacy and safety of eliapixant in diabetic neuropathic pain and prediction of placebo responders with an exploratory novel algorithm: results from the randomized controlled phase 2a PUCCINI study. Pain 2024; 165:785-795. [PMID: 37851336 DOI: 10.1097/j.pain.0000000000003085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 08/18/2023] [Indexed: 10/19/2023]
Abstract
ABSTRACT Phase 2a of the PUCCINI study was a placebo-controlled, double-blind, parallel-group, multicenter, proof-of-concept study evaluating the efficacy and safety of the selective P2X3 antagonist eliapixant in patients with diabetic neuropathic pain (DNP) ( ClinicalTrials.gov NCT04641273). Adults with type 1 or type 2 diabetes mellitus with painful distal symmetric sensorimotor neuropathy of >6 months' duration and neuropathic pain were enrolled and randomized 1:1 to 150 mg oral eliapixant twice daily or placebo for 8 weeks. The primary endpoint was change from baseline in weekly mean 24-hour average pain intensity score at week 8. In total, 135 participants completed treatment, 67 in the eliapixant group and 68 in the placebo group. At week 8, the change from baseline in posterior mean 24-hour average pain intensity score (90% credible interval) in the eliapixant group was -1.56 (-1.95, -1.18) compared with -2.17 (-2.54, -1.80) for the placebo group. The mean treatment difference was 0.60 (0.06, 1.14) in favor of placebo. The use of a model-based framework suggests that various factors may contribute to the placebo-responder profile. Adverse events were mostly mild or moderate in severity and occurred in 51% of the eliapixant group and 48% of the placebo group. As the primary endpoint was not met, the PUCCINI study was terminated after completion of phase 2a and did not proceed to phase 2b. In conclusion, selective P2X3 antagonism in patients with DNP did not translate to any relevant improvement in different pain intensity outcomes compared with placebo. Funding: Bayer AG.
Collapse
Affiliation(s)
- Didier Bouhassira
- INSERM U987, APHP, CHU Ambroise Paré, UVSQ, Paris-Saclay, Boulogne-Billancourt, France
| | - Solomon Tesfaye
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Arnab Sarkar
- Research & Development, Pharmaceuticals, Bayer AG, Berlin, Germany
| | | | - Brigitte Stemper
- Research & Development, Pharmaceuticals, Bayer AG, Berlin, Germany
- Department of Neurology, University Erlangen Nürnberg, Erlangen, Germany
| | - Ralf Baron
- Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany
| |
Collapse
|
|
6
|
Aziz N, Dash B, Wal P, Kumari P, Joshi P, Wal A. New Horizons in Diabetic Neuropathies: An Updated Review on their Pathology, Diagnosis, Mechanism, Screening Techniques, Pharmacological, and Future Approaches. Curr Diabetes Rev 2024; 20:e201023222416. [PMID: 37867268 DOI: 10.2174/0115733998242299231011181615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 07/16/2023] [Accepted: 08/25/2023] [Indexed: 10/24/2023]
Abstract
BACKGROUND One of the largest problems for global public health is diabetes mellitus (DM) and its micro and macrovascular consequences. Although prevention, diagnosis, and treatment have generally improved, its incidence is predicted to keep rising over the coming years. Due to the intricacy of the molecular mechanisms, which include inflammation, oxidative stress, and angiogenesis, among others, discovering treatments to stop or slow the course of diabetic complications is still a current unmet need. METHODS The pathogenesis and development of diabetic neuropathies may be explained by a wide variety of molecular pathways, hexosamine pathways, such as MAPK pathway, PARP pathway, oxidative stress pathway polyol (sorbitol) pathway, cyclooxygenase pathway, and lipoxygenase pathway. Although diabetic neuropathies can be treated symptomatically, there are limited options for treating the underlying cause. RESULT Various pathways and screening models involved in diabetic neuropathies are discussed, along with their possible outcomes. Moreover, both medicinal and non-medical approaches to therapy are also explored. CONCLUSION This study highlights the probable involvement of several processes and pathways in the establishment of diabetic neuropathies and presents in-depth knowledge of new therapeutic approaches intended to stop, delay, or reverse different types of diabetic complications.
Collapse
Affiliation(s)
- Namra Aziz
- Pranveer Singh Institute of Technology (Pharmacy), Bhauti, Kanpur 209305, UP, India
| | - Biswajit Dash
- Department of Pharmaceutical Technology, School of Medical Sciences, ADAMAS University, Kolkata 700 126, West Bengal, India
| | - Pranay Wal
- Pranveer Singh Institute of Technology (Pharmacy), Bhauti, Kanpur 209305, UP, India
| | - Prachi Kumari
- Pranveer Singh Institute of Technology (Pharmacy), Bhauti, Kanpur 209305, UP, India
| | - Poonam Joshi
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun 248007, Uttarakhand, India
| | - Ankita Wal
- Pranveer Singh Institute of Technology (Pharmacy), Bhauti, Kanpur 209305, UP, India
| |
Collapse
|
|
7
|
Tesfaye S, Kempler P. Conventional management and current guidelines for painful diabetic neuropathy. Diabetes Res Clin Pract 2023; 206 Suppl 1:110765. [PMID: 38245323 DOI: 10.1016/j.diabres.2023.110765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 05/30/2023] [Indexed: 01/22/2024]
Abstract
Painful Diabetic Peripheral Neuropathy (PDN) is common, affecting around a quarter of patients with both type 1 and type 2 diabetes, and can lead to significant curtailment of functionality and quality of life. Patients may present with unremitting burning, aching or "electric-shock" type pains in their feet, legs and later, in the hands. Conventional management approaches must focus not only on pain relief, but also on concurrent sleep problems, mood disorders and functionality. The mainstay of treatment is pharmacotherapy. Most current international guidelines recommend a choice of four drugs: amitriptyline, duloxetine, pregabalin or gabapentin, as initial treatment for PDN. Recent evidence from the OPTION-DM trial demonstrated that these drugs and their combinations have equivalent efficacy. Moreover, combination treatment provided significant pain relief to patients with inadequate response to the maximum tolerated dose of monotherapy. PDN refractory to pharmacotherapy can be treated with capsaicin 8% or high frequency spinal cord stimulation.
Collapse
Affiliation(s)
- Solomon Tesfaye
- Diabetes Research Department, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.
| | - Peter Kempler
- Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| |
Collapse
|
|
8
|
Park M, Choi S, Han S, Shin W, Kim A, Han S, Kim B, Lim Y, Yoo H. Pharmacokinetic properties of a new sustained-release pregabalin tablet in subjects with reduced renal function. Transl Clin Pharmacol 2023; 31:226-237. [PMID: 38197000 PMCID: PMC10772055 DOI: 10.12793/tcp.2023.31.e20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/18/2023] [Accepted: 12/19/2023] [Indexed: 01/11/2024] Open
Abstract
A new sustained-release (SR) pregabalin tablet, YHD1119, was formulated for once-daily dosing. In the current study, we aimed to evaluate the pharmacokinetics of YHD1119 tablets in patients with reduced renal function. Subjects were grouped by creatinine clearance: > 60 mL/min/1.73m2 (Cohort A) and 30-60 mL/min/1.73m2 (Cohort B). Eight subjects in Cohort A received a YHD1119 75 mg tablet (Y75T) and a YHD1119 150 mg tablet (Y150T) in each period, and eight subjects in Cohort B received a Y75T. Non-compartment analysis and population pharmacokinetic analysis using a one-compartment model with first-order elimination and first-order absorption with lag time were performed. Sixteen subjects completed the study. The geometric mean ratio (GMR) (90% confidence intervals [CI]) for maximum concentration (Cmax), and area under the concentration-time profile from 0 to the last measurable time (AUClast) after Y75T of Cohort B to those of Y75T of Cohort A were 1.2273 (1.0245-1.4701), and 2.4146 (1.8142-3.2138), respectively. The GMR (90% CI) for Cmax, and AUClast after Y75T of Cohort B to those of Y150T of Cohort A were 0.6476 (0.5229-0.8021), and 1.1471 (0.8418-1.5632), respectively. Simulated steady-steady pregabalin concentrations after once-daily Y75T dosing in subjects with eGFR 45 mL/min/1.73 m2 were within the range of steady-state concentrations simulated after once-daily Y150T dosing in subjects with eGFR 90 mL/min/1.73 m2. The total pregabalin exposure of Y75T in patients with moderate renal impairment was comparable with that of Y150T in subjects with near-normal renal function. Trial Registration ClinicalTrials.gov Identifier: NCT05012436.
Collapse
Affiliation(s)
- Maria Park
- Department of Clinical Pharmacology and Therapeutics, The Catholic University of Korea Seoul St. Mary’s Hospital, Seoul 06591, Korea
- Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Suein Choi
- Department of Clinical Pharmacology and Therapeutics, The Catholic University of Korea Seoul St. Mary’s Hospital, Seoul 06591, Korea
- Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Sungpil Han
- Department of Clinical Pharmacology and Therapeutics, The Catholic University of Korea Seoul St. Mary’s Hospital, Seoul 06591, Korea
- Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Wonsuk Shin
- Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, Seongnam 13520, Korea
- Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine, Seongnam 13520, Korea
| | - Anhye Kim
- Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, Seongnam 13520, Korea
- Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine, Seongnam 13520, Korea
| | - Seunghoon Han
- Department of Clinical Pharmacology and Therapeutics, The Catholic University of Korea Seoul St. Mary’s Hospital, Seoul 06591, Korea
- Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Bomin Kim
- Clinical Development and Medical Division, Yuhan Corporation, Seoul 06927, Korea
| | - Yeji Lim
- Clinical Development and Medical Division, Yuhan Corporation, Seoul 06927, Korea
| | - Hyounggyoon Yoo
- Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, Seongnam 13520, Korea
- Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine, Seongnam 13520, Korea
| |
Collapse
|
|
9
|
Cangemi DJ, Lacy BE. Gastroparesis: Myths, Misconceptions, and Management. Clin Exp Gastroenterol 2023; 16:65-78. [PMID: 37303313 PMCID: PMC10257400 DOI: 10.2147/ceg.s362879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 03/29/2023] [Indexed: 06/13/2023] Open
Abstract
Gastroparesis (GP), a historically vexing disorder characterized by symptoms of nausea, vomiting, abdominal pain, early satiety, and/or bloating, in the setting of an objective delay in gastric emptying, is often difficult to treat and carries a tremendous burden on the quality of patients' lives, as well as the healthcare system in general. Though the etiology of GP has been fairly well defined, much work has been done recently to better understand the pathophysiology of GP, as well as to identify novel effective and safe treatment options. As our understanding of GP has evolved, many myths and misconceptions still abound in this rapidly changing field. The goal of this review is to identify myths and misconceptions regarding the etiology, pathophysiology, diagnosis, and treatment of GP, in the context of the latest research findings which have shaped our current understanding of GP. Recognition and dispelling of such myths and misconceptions is critical to moving the field forward and ultimately advancing the clinical management of what will hopefully become a better understood and more manageable disorder in the future.
Collapse
Affiliation(s)
- David J Cangemi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Brian E Lacy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| |
Collapse
|
|
10
|
Kang SM, Hong JH, Ku BJ. A randomized, active-controlled, parallel, open-label, multicenter, phase 4 study to compare the efficacy and safety of pregabalin sustained release tablet and pregabalin immediate release capsule in type II diabetic patients with peripheral neuropathic pain. Medicine (Baltimore) 2023; 102:e33701. [PMID: 37115054 PMCID: PMC10145715 DOI: 10.1097/md.0000000000033701] [Citation(s) in RCA: 1] [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: 04/13/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND Diabetic peripheral polyneuropathy is the most common chronic complication of type 2 diabetes. Neuropathic pain is challenging to manage, and various drugs are required to control it, decreasing treatment adherence. Pregabalin, a ligand that binds to alpha-2-delta subunits of the presynaptic calcium channel, has been approved by the Food and Drug Administration for the treatment of diabetic neuropathic pain. In this study, we will compare the efficacy, safety, treatment satisfaction, and compliance between pregabalin sustained-release (SR) tablets and pregabalin immediate-release (IR) capsules in type 2 diabetic patients with peripheral neuropathic pain. METHODS This study is a randomized, active-controlled, parallel, open-label, multicenter, phase 4 clinical trial (trial registration NCT05624853). Type 2 diabetic patients with glycosylated hemoglobin below 10% and peripheral neuropathic pain who have been taking pregabalin 150 mg/d or more for more than 4 weeks will be randomly assigned to pregabalin SR tablet (150 mg once a day, n = 65) or pregabalin IR capsule (75 mg twice a day, n = 65) therapy for 8 weeks. The primary outcome will be the efficacy of SR pregabalin after 8 weeks of treatment, which will be assessed by visual analog scale measurements. The secondary outcomes will include changes in several parameters, such as quality of life, treatment satisfaction, quality of sleep, and drug compliance. DISCUSSION In thus study, we aim to demonstrate that pregabalin SR tablets are associated with better compliance and satisfaction compared with pregabalin IR capsules, despite similar efficacy.
Collapse
Affiliation(s)
- Seon Mee Kang
- Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, South Korea
| | - Jun Hwa Hong
- Department of Internal Medicine, Eulji University Hospital, Eulji University School of Medicine, Daejeon, South Korea
| | - Bon Jeong Ku
- Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, South Korea
| |
Collapse
|
|
11
|
K. K, Dutt S, Rattan P, Dadhania A, Gupta R, Joshi D, Kakkad A, Makwana A, Jha P. Fixed dose combination of low dose pregabalin and duloxetine, or pregabalin monotherapy for neuropathic pain: A double-blind, randomized, parallel-group study. F1000Res 2023; 12:353. [PMID: 38618021 PMCID: PMC11016171 DOI: 10.12688/f1000research.130345.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/13/2023] [Indexed: 04/16/2024] Open
Abstract
Background: Treatment of neuropathic pain is challenging. Pregabalin and duloxetine are used as first-line therapy. Various international guidelines recommend a combination of first-line agents for the management of neuropathic pain. The objective of this study was to evaluate the efficacy and safety of a fixed-dose combination (FDC) of low-dose pregabalin and duloxetine compared to pregabalin monotherapy at week 7 in patients with moderate to severe neuropathic pain. Methods: This was a phase 3, randomized, double-blind, double-dummy parallel-group non-inferiority study conducted at 17 sites across India. Three hundred and twenty-eight adult patients with moderate to severe neuropathic pain were randomized in a ratio of 1:1 to receive a FDC of pregabalin and duloxetine or pregabalin monotherapy for 7 weeks followed by a one-week follow-up. The pregabalin-duloxetine combination was initiated at 50 plus 20 mg per day and gradually titrated to a maximum of 75mg plus 30mg twice daily. Pregabalin was initiated at 75mg/day and gradually titrated to a maximum of 150mg twice daily. The main efficacy outcome was a mean change in pain intensity at the end of 7 weeks. Results: Two hundred and ninety-eight patients completed the study, 148 in the pregabalin-duloxetine group and 150 in the pregabalin group. The mean change in daily pain at 7 weeks was as follows: -4.49 with FDC and -4.66 with pregabalin (p<0.0001). The non-inferiority of a low-dose FDC compared to pregabalin monotherapy was demonstrated at the end of the study. The incidence of dizziness and somnolence was comparable between both treatments. A higher frequency of peripheral oedema was observed with pregabalin monotherapy than in the FDC group (p>0.05). Conclusions: A FDC of low doses of pregabalin and duloxetine and high dose of pregabalin monotherapy achieved similar analgesia with dizziness, and somnolence as the most frequent adverse event. Trial registration: CTRI/2020/09/027555.
Collapse
Affiliation(s)
- Krishnaprasad K.
- Medical Services, Torrent Pharmaceuticals Limited, Gandhinagar, Gujrat, 382428, India
| | - Sunil Dutt
- Torrent Pharmaceuticals Limited, Torrent Research Center, Bhat, Gandhinagar, Gujarat, 382428, India
| | - Pankaj Rattan
- Torrent Pharmaceuticals Limited, Torrent Research Center, Bhat, Gandhinagar, Gujarat, 382428, India
| | - Ankit Dadhania
- Torrent Pharmaceuticals Limited, Torrent Research Center, Bhat, Gandhinagar, Gujarat, 382428, India
| | - Ram Gupta
- Torrent Pharmaceuticals Limited, Torrent Research Center, Bhat, Gandhinagar, Gujarat, 382428, India
| | - Deepa Joshi
- Torrent Pharmaceuticals Limited, Torrent Research Center, Bhat, Gandhinagar, Gujarat, 382428, India
| | - Ashutosh Kakkad
- Medical Services, Torrent Pharmaceuticals Limited, Gandhinagar, Gujrat, 382428, India
| | - Altaf Makwana
- Medical Services, Torrent Pharmaceuticals Limited, Gandhinagar, Gujrat, 382428, India
| | - Pankaj Jha
- Medical Services, Torrent Pharmaceuticals Limited, Gandhinagar, Gujrat, 382428, India
| |
Collapse
|
|
12
|
Stem Cell Therapy in Diabetic Polyneuropathy: Recent Advancements and Future Directions. Brain Sci 2023; 13:brainsci13020255. [PMID: 36831798 PMCID: PMC9954679 DOI: 10.3390/brainsci13020255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/24/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Diabetic polyneuropathy (DPN) is the most frequent, although neglected, complication of long-term diabetes. Nearly 30% of hospitalized and 20% of community-dwelling patients with diabetes suffer from DPN; the incidence rate is approximately 2% annually. To date, there has been no curable therapy for DPN. Under these circumstances, cell therapy may be a vital candidate for the treatment of DPN. The epidemiology, classification, and treatment options for DPN are disclosed in the current review. Cell-based therapies using bone marrow-derived cells, embryonic stem cells, pluripotent stem cells, endothelial progenitor cells, mesenchymal stem cells, or dental pulp stem cells are our primary concern, which may be a useful treatment option to ease or to stop the progression of DPN. The importance of cryotherapies for treating DPN has been observed in several studies. These findings may help for the future researchers to establish more focused, accurate, effective, alternative, and safe therapy to reduce DPN. Cell-based therapy might be a permanent solution in the treatment and management of diabetes-induced neuropathy.
Collapse
|
|
13
|
Tesfaye S, Sloan G, White D, Bradburn M, Bouhassira D, Selvarajah D. Who really benefits from drug combinations and long titrations for pain? - Authors' reply. Lancet 2023; 401:192-193. [PMID: 36681412 DOI: 10.1016/s0140-6736(23)00057-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 12/19/2022] [Indexed: 01/21/2023]
Affiliation(s)
- Solomon Tesfaye
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK; School of Health and Related Research, and Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
| | - Gordon Sloan
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK
| | - David White
- Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Mike Bradburn
- Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | | | - Dinesh Selvarajah
- School of Health and Related Research, and Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| |
Collapse
|
|
14
|
Nozawa K, Karasawa Y, Shidahara Y, Ushida T. Efficacy of Combination Therapy with Pregabalin in Neuropathic Pain: A Preclinical Study in the Rat L5 Spinal Nerve Ligation Model. J Pain Res 2022; 15:3469-3478. [PMID: 36338796 PMCID: PMC9635478 DOI: 10.2147/jpr.s383981] [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: 07/27/2022] [Accepted: 10/27/2022] [Indexed: 11/27/2022] Open
Abstract
PURPOSE Neuropathic pain is sometimes difficult to manage because of limited efficacy of analgesic monotherapy even at high doses. Combination therapy may help address this issue, but there is little evidence for its effectiveness. Therefore, we evaluated the efficacy of combination therapy with pregabalin, an anchor drug for treating neuropathic pain, using the rat L5 spinal nerve ligation model. METHODS Experiments were performed on four-week-old L5 spinal nerve ligated male Sprague-Dawley rats. Mechanical allodynia was assessed using the von Frey test, where the 50% withdrawal threshold was evaluated for five drugs: pregabalin, duloxetine, venlafaxine, tramadol, and celecoxib. The single-drug experiment included 112 rats, where each drug was tested independently. Median effective doses (ED50s) were determined. Combinations of pregabalin with each of the other four drugs were tested (n=84). The 50% withdrawal threshold in the von Frey test was evaluated. The ED50 of each combination was determined experimentally. Isobolographic analyses were conducted to assess the synergistic potential of the drug combinations, excluding pregabalin-celecoxib, since the ED50 of celecoxib could not be determined. RESULTS In the single-drug experiment, all drugs except celecoxib resulted in a dose-dependent increase in the 50% withdrawal threshold 2 h after administration, with a maximum possible effect ranging from 4.4% to 79.6%. Similarly, all pregabalin combinations demonstrated a dose-dependent increase in the 50% withdrawal threshold, with pregabalin-tramadol showing the greatest increment. Isobolographic analysis of this combination revealed synergistic effects. Specifically, the combination index was γ=0.4 (<1). Combinations of pregabalin with duloxetine and venlafaxine demonstrated additive (γ=0.9) and antagonistic effects (γ=2.0), respectively. CONCLUSION This study demonstrated that combination of pregabalin with tramadol has synergistic antiallodynic effects, while that with duloxetine has additive effects. Moreover, pregabalin combined with venlafaxine was potentially antagonistic. Pregabalin combined with tramadol may serve as a promising drug combination for the effective management of neuropathic pain.
Collapse
Affiliation(s)
- Kazutaka Nozawa
- Medical Affairs, Viatris Pharmaceuticals Japan Inc., Minato-ku, Tokyo, Japan,Correspondence: Kazutaka Nozawa, Medical Affairs, Viatris Pharmaceuticals Japan Inc, Minato-ku, Tokyo, Japan, Tel +81 80-5001-3029, Email
| | - Yusuke Karasawa
- Medical Affairs, Viatris Pharmaceuticals Japan Inc., Minato-ku, Tokyo, Japan
| | - Yuka Shidahara
- Bioscience Business Division, KAC Co., Ltd, Ritto, Shiga, Japan
| | - Takahiro Ushida
- Multidisciplinary Pain Center, Aichi Medical University, Nagakute, Aichi, Japan
| |
Collapse
|
|
15
|
Tesfaye S, Sloan G, Petrie J, White D, Bradburn M, Young T, Rajbhandari S, Sharma S, Rayman G, Gouni R, Alam U, Julious SA, Cooper C, Loban A, Sutherland K, Glover R, Waterhouse S, Turton E, Horspool M, Gandhi R, Maguire D, Jude E, Ahmed SH, Vas P, Hariman C, McDougall C, Devers M, Tsatlidis V, Johnson M, Bouhassira D, Bennett DL, Selvarajah D. Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT. Health Technol Assess 2022; 26:1-100. [PMID: 36259684 PMCID: PMC9589396 DOI: 10.3310/rxuo6757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND The mainstay of treatment for diabetic peripheral neuropathic pain is pharmacotherapy, but the current National Institute for Health and Care Excellence guideline is not based on robust evidence, as the treatments and their combinations have not been directly compared. OBJECTIVES To determine the most clinically beneficial, cost-effective and tolerated treatment pathway for diabetic peripheral neuropathic pain. DESIGN A randomised crossover trial with health economic analysis. SETTING Twenty-one secondary care centres in the UK. PARTICIPANTS Adults with diabetic peripheral neuropathic pain with a 7-day average self-rated pain score of ≥ 4 points (Numeric Rating Scale 0-10). INTERVENTIONS Participants were randomised to three commonly used treatment pathways: (1) amitriptyline supplemented with pregabalin, (2) duloxetine supplemented with pregabalin and (3) pregabalin supplemented with amitriptyline. Participants and research teams were blinded to treatment allocation, using over-encapsulated capsules and matching placebos. Site pharmacists were unblinded. OUTCOMES The primary outcome was the difference in 7-day average 24-hour Numeric Rating Scale score between pathways, measured during the final week of each pathway. Secondary end points included 7-day average daily Numeric Rating Scale pain score at week 6 between monotherapies, quality of life (Short Form questionnaire-36 items), Hospital Anxiety and Depression Scale score, the proportion of patients achieving 30% and 50% pain reduction, Brief Pain Inventory - Modified Short Form items scores, Insomnia Severity Index score, Neuropathic Pain Symptom Inventory score, tolerability (scale 0-10), Patient Global Impression of Change score at week 16 and patients' preferred treatment pathway at week 50. Adverse events and serious adverse events were recorded. A within-trial cost-utility analysis was carried out to compare treatment pathways using incremental costs per quality-adjusted life-years from an NHS and social care perspective. RESULTS A total of 140 participants were randomised from 13 UK centres, 130 of whom were included in the analyses. Pain score at week 16 was similar between the arms, with a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for duloxetine supplemented with pregabalin compared with amitriptyline supplemented with pregabalin, a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for pregabalin supplemented with amitriptyline compared with amitriptyline supplemented with pregabalin and a mean difference of 0.0 points (98.3% confidence interval -0.4 to 0.4 points) for pregabalin supplemented with amitriptyline compared with duloxetine supplemented with pregabalin. Results for tolerability, discontinuation and quality of life were similar. The adverse events were predictable for each drug. Combination therapy (weeks 6-16) was associated with a further reduction in Numeric Rating Scale pain score (mean 1.0 points, 98.3% confidence interval 0.6 to 1.3 points) compared with those who remained on monotherapy (mean 0.2 points, 98.3% confidence interval -0.1 to 0.5 points). The pregabalin supplemented with amitriptyline pathway had the fewest monotherapy discontinuations due to treatment-emergent adverse events and was most commonly preferred (most commonly preferred by participants: amitriptyline supplemented with pregabalin, 24%; duloxetine supplemented with pregabalin, 33%; pregabalin supplemented with amitriptyline, 43%; p = 0.26). No single pathway was superior in cost-effectiveness. The incremental gains in quality-adjusted life-years were small for each pathway comparison [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -0.002 (95% confidence interval -0.011 to 0.007) quality-adjusted life-years, amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline -0.006 (95% confidence interval -0.002 to 0.014) quality-adjusted life-years and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline 0.007 (95% confidence interval 0.0002 to 0.015) quality-adjusted life-years] and incremental costs over 16 weeks were similar [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -£113 (95% confidence interval -£381 to £90), amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £155 (95% confidence interval -£37 to £625) and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £141 (95% confidence interval -£13 to £398)]. LIMITATIONS Although there was no placebo arm, there is strong evidence for the use of each study medication from randomised placebo-controlled trials. The addition of a placebo arm would have increased the duration of this already long and demanding trial and it was not felt to be ethically justifiable. FUTURE WORK Future research should explore (1) variations in diabetic peripheral neuropathic pain management at the practice level, (2) how OPTION-DM (Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus) trial findings can be best implemented, (3) why some patients respond to a particular drug and others do not and (4) what options there are for further treatments for those patients on combination treatment with inadequate pain relief. CONCLUSIONS The three treatment pathways appear to give comparable patient outcomes at similar costs, suggesting that the optimal treatment may depend on patients' preference in terms of side effects. TRIAL REGISTRATION The trial is registered as ISRCTN17545443 and EudraCT 2016-003146-89. FUNDING This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in Health Technology Assessment; Vol. 26, No. 39. See the NIHR Journals Library website for further project information.
Collapse
Affiliation(s)
- Solomon Tesfaye
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Department of Oncology and Human Metabolism, Medical School, University of Sheffield, Sheffield, UK
| | - Gordon Sloan
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Jennifer Petrie
- Clinical Trials Research Unit, University of Sheffield, School of Health and Related Research (ScHARR), Sheffield, UK
| | - David White
- Clinical Trials Research Unit, University of Sheffield, School of Health and Related Research (ScHARR), Sheffield, UK
| | - Mike Bradburn
- Clinical Trials Research Unit, University of Sheffield, School of Health and Related Research (ScHARR), Sheffield, UK
| | - Tracey Young
- School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
| | | | - Sanjeev Sharma
- East Suffolk and North Essex NHS Foundation Trust, Ipswich, UK
| | - Gerry Rayman
- East Suffolk and North Essex NHS Foundation Trust, Ipswich, UK
| | | | - Uazman Alam
- University of Liverpool, Liverpool, UK
- Liverpool University Hospital NHS Foundation Trust, Liverpool, UK
| | - Steven A Julious
- Medical Statistics Group, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
| | - Cindy Cooper
- Clinical Trials Research Unit, University of Sheffield, School of Health and Related Research (ScHARR), Sheffield, UK
| | - Amanda Loban
- Clinical Trials Research Unit, University of Sheffield, School of Health and Related Research (ScHARR), Sheffield, UK
| | - Katie Sutherland
- Clinical Trials Research Unit, University of Sheffield, School of Health and Related Research (ScHARR), Sheffield, UK
| | - Rachel Glover
- Clinical Trials Research Unit, University of Sheffield, School of Health and Related Research (ScHARR), Sheffield, UK
| | - Simon Waterhouse
- Clinical Trials Research Unit, University of Sheffield, School of Health and Related Research (ScHARR), Sheffield, UK
| | - Emily Turton
- Clinical Trials Research Unit, University of Sheffield, School of Health and Related Research (ScHARR), Sheffield, UK
| | | | - Rajiv Gandhi
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | | | - Edward Jude
- Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton under Lyne, UK
- University of Manchester, Manchester, UK
| | - Syed Haris Ahmed
- University of Liverpool, Liverpool, UK
- Countess of Chester Hospital NHS Foundation Trust, Chester, UK
| | - Prashanth Vas
- King's College Hospital NHS Foundation Trust, London, UK
| | | | | | | | | | | | | | - David L Bennett
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Dinesh Selvarajah
- Department of Oncology and Human Metabolism, Medical School, University of Sheffield, Sheffield, UK
| |
Collapse
|
|
16
|
Kitano Y, Shinozuka T. Inhibition of Na V1.7: the possibility of ideal analgesics. RSC Med Chem 2022; 13:895-920. [PMID: 36092147 PMCID: PMC9384491 DOI: 10.1039/d2md00081d] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 07/25/2022] [Indexed: 08/03/2023] Open
Abstract
The selective inhibition of NaV1.7 is a promising strategy for developing novel analgesic agents with fewer adverse effects. Although the potent selective inhibition of NaV1.7 has been recently achieved, multiple NaV1.7 inhibitors failed in clinical development. In this review, the relationship between preclinical in vivo efficacy and NaV1.7 coverage among three types of voltage-gated sodium channel (VGSC) inhibitors, namely conventional VGSC inhibitors, sulphonamides and acyl sulphonamides, is discussed. By demonstrating the PK/PD discrepancy of preclinical studies versus in vivo models and clinical results, the potential reasons behind the disconnect between preclinical results and clinical outcomes are discussed together with strategies for developing ideal analgesic agents.
Collapse
Affiliation(s)
- Yutaka Kitano
- R&D Division, Daiichi Sankyo Co., Ltd. 1-2-58 Hiromachi Shinagawa-ku Tokyo 140-8710 Japan
| | - Tsuyoshi Shinozuka
- R&D Division, Daiichi Sankyo Co., Ltd. 1-2-58 Hiromachi Shinagawa-ku Tokyo 140-8710 Japan
| |
Collapse
|
|
17
|
Fang XX, Wang H, Song HL, Wang J, Zhang ZJ. Neuroinflammation Involved in Diabetes-Related Pain and Itch. Front Pharmacol 2022; 13:921612. [PMID: 35795572 PMCID: PMC9251344 DOI: 10.3389/fphar.2022.921612] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 05/12/2022] [Indexed: 12/25/2022] Open
Abstract
Diabetes mellitus (DM) is a global epidemic with increasing incidence, which results in diverse complications, seriously affects the patient quality of life, and brings huge economic burdens to society. Diabetic neuropathy is the most common chronic complication of DM, resulting in neuropathic pain and chronic itch. The precise mechanisms of diabetic neuropathy have not been fully clarified, hindering the exploration of novel therapies for diabetic neuropathy and its terrible symptoms such as diabetic pain and itch. Accumulating evidence suggests that neuroinflammation plays a critical role in the pathophysiologic process of neuropathic pain and chronic itch. Indeed, researchers have currently made significant progress in knowing the role of glial cells and the pro-inflammatory mediators produced from glial cells in the modulation of chronic pain and itch signal processing. Here, we provide an overview of the current understanding of neuroinflammation in contributing to the sensitization of the peripheral nervous system (PNS) and central nervous system (CNS). In addition, we also summarize the inflammation mechanisms that contribute to the pathogenesis of diabetic itch, including activation of glial cells, oxidative stress, and pro-inflammatory factors. Targeting excessive neuroinflammation may provide potential and effective therapies for the treatment of chronic neuropathic pain and itch in DM.
Collapse
Affiliation(s)
- Xiao-Xia Fang
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
- Department of Medical Functional Laboratory, School of Medicine, Nantong University, Nantong, China
| | - Heng Wang
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
| | - Hao-Lin Song
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
| | - Juan Wang
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
| | - Zhi-Jun Zhang
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
| |
Collapse
|
|
18
|
Jain SM, Balamurugan R, Tandon M, Mozaffarian N, Gudi G, Salhi Y, Holland R, Freeman R, Baron R. Randomized, double-blind, placebo-controlled trial of ISC 17536, an oral inhibitor of transient receptor potential ankyrin 1, in patients with painful diabetic peripheral neuropathy: impact of preserved small nerve fiber function. Pain 2022; 163:e738-e747. [PMID: 34490850 PMCID: PMC9100440 DOI: 10.1097/j.pain.0000000000002470] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 08/10/2021] [Accepted: 08/23/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Patients with chronic pain syndromes, such as those with painful peripheral neuropathy due to diabetes mellitus, have limited treatment options and suffer ongoing attrition of their quality of life. Safer and more effective treatment options are needed. One therapeutic approach encompasses phenotypic characterization of the neuropathic pain subtype, combined with the selection of agents that act on relevant mechanisms. ISC 17536 is a novel, orally available inhibitor of the widely expressed pain receptor, transient receptor potential ankyrin 1, which mediates nociceptive signaling in peripheral small nerve fibers. In this randomized, placebo-controlled, proof-of-concept trial, we assessed the safety and efficacy of 28-day administration of ISC 17536 in 138 patients with chronic, painful diabetic peripheral neuropathy and used quantitative sensory testing to characterize the baseline phenotype of patients. The primary end point was the change from baseline to end of treatment in the mean 24-hour average pain intensity score based on an 11-point pain intensity numeric rating scale. The study did not meet the primary end point in the overall patient population. However, statistically significant and clinically meaningful improvement in pain were seen with ISC 17536 in an exploratory hypothesis-generating subpopulation of patients with preserved small nerve fiber function defined by quantitative sensory testing. These results may provide a mechanistic basis for targeted therapy in specific pain phenotypes in line with current approaches of "precision medicine" or personalized pain therapeutics. The hypothesis is planned to be tested in a larger phase 2 study.
Collapse
Affiliation(s)
| | | | - Monika Tandon
- Clinical Sciences, Glenmark Pharmaceuticals Limited, Mumbai, India
| | | | - Girish Gudi
- Ichnos Sciences, Inc, New York, NY, United States
| | - Yacine Salhi
- Ichnos Sciences, Inc, New York, NY, United States
| | - Robert Holland
- Early Clinical Development Consulting Ltd, Macclesfield, United Kingdom
| | - Roy Freeman
- Department of Neurology, Harvard Medical School, Boston, MA, United States
| | - Ralf Baron
- Division of Neurological Pain Research and Therapy, Universitätsklinikum Schleswig-Holstein, Campus-Kiel, Germany
| |
Collapse
|
|
19
|
Friedrich C, Francke K, Gashaw I, Scheerans C, Klein S, Fels L, Smith JA, Hummel T, Morice A. Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study. Clin Pharmacokinet 2022; 61:1143-1156. [PMID: 35624408 PMCID: PMC9349145 DOI: 10.1007/s40262-022-01126-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/30/2022] [Indexed: 12/12/2022]
Abstract
Background and Objective There is no licensed treatment for refractory chronic cough; off-label therapies have limited efficacy and can produce adverse effects. Excessive adenosine triphosphate signaling via P2X3 receptors is implicated in refractory chronic cough, and selective P2X3 receptor antagonists such as eliapixant (BAY 1817080) are under investigation. The objective of the study was to investigate the safety and tolerability of ascending repeated oral doses of eliapixant in healthy volunteers. Methods We conducted a repeated-dose, double-blind, randomized, placebo-controlled study in 47 healthy male individuals. Subjects received repeated twice-daily ascending oral doses of eliapixant (10, 50, 200, and 750 mg) or placebo for 2 weeks. The primary outcome was frequency and severity of adverse events. Other outcomes included pharmacokinetics and evaluation of taste disturbances, which have occurred with the less selective P2X3 receptor antagonist gefapixant. Results Peak plasma concentrations of eliapixant were reached 3–4 h after administration of the first and subsequent doses. With multiple dosing, steady-state plasma concentrations were reached after ~ 6 days, and plasma concentrations predicted to achieve ≥ 80% P2X3 receptor occupancy (the level required for efficacy) were reached at 200 and 750 mg. Increases in plasma concentrations with increasing doses were less than dose proportional. After multiple dosing, mean plasma concentrations of eliapixant showed low peak–trough fluctuations and were similar for 200- and 750-mg doses. Eliapixant was well tolerated with a low incidence of taste-related adverse events. Conclusions Eliapixant (200 and 750 mg) produced plasma concentrations that cover the predicted therapeutic threshold over 24 h, with good safety and tolerability. These results enabled eliapixant to progress to clinical trials in patients with refractory chronic cough. Clinical Trial Registration Clinicaltrials.gov: NCT03310645 (initial registration: 16 October, 2017). Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01126-1. There are few effective treatments for patients with a long-term (chronic) cough. It is thought that chronic cough is caused by nerves becoming oversensitive, wrongly causing a cough when there is no need. We tested a new drug called eliapixant in 47 healthy men. Eliapixant reduces the excessive nerve signaling responsible for chronic cough. We looked for side effects of eliapixant and measured how it behaves in the body. In particular we looked for side effects relating to the sense of taste because gefapixant, a similar drug to eliapixant, can affect taste. Participants took one of four eliapixant doses or a placebo twice daily for 2 weeks. The highest levels of eliapixant in the blood were seen 3–4 h after taking the drug, and stable concentrations were seen after about 6 days. At the two highest doses, eliapixant reached concentrations in the body that should be high enough to work in patients with chronic cough. Side effects were generally similar between eliapixant and placebo. Taste-related side effects were mild and went away without needing treatment. The positive results of this study meant that eliapixant could be tested in patients with chronic cough.
Collapse
Affiliation(s)
- Christian Friedrich
- Bayer AG Research & Development, Pharmaceuticals Clinical Pharmacology, 1 Building M004, 13353, Berlin, Germany.
| | - Klaus Francke
- Bayer AG Research & Development, Pharmaceuticals Clinical Pharmacology, 1 Building M004, 13353, Berlin, Germany
| | - Isabella Gashaw
- Bayer AG Research & Development, Pharmaceuticals Clinical Pharmacology, 1 Building M004, 13353, Berlin, Germany.,Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
| | - Christian Scheerans
- Bayer AG Research & Development, Pharmaceuticals Clinical Pharmacology, 1 Building M004, 13353, Berlin, Germany
| | - Stefan Klein
- Bayer AG Research & Development, Pharmaceuticals Clinical Pharmacology, 1 Building M004, 13353, Berlin, Germany
| | - Lueder Fels
- Bayer AG Research & Development, Pharmaceuticals Clinical Pharmacology, 1 Building M004, 13353, Berlin, Germany
| | - Jaclyn A Smith
- University of Manchester, Manchester University NHS Foundation Trust and Manchester Academic Health Science Centre, Manchester, UK
| | - Thomas Hummel
- Smell and Taste Clinic, Department of Otorhinolaryngology, TU Dresden, Dresden, Germany
| | - Alyn Morice
- Centre for Clinical Sciences, Hull York Medical School, University of Hull, Hull, UK
| |
Collapse
|
|
20
|
Ziegler D, Tesfaye S, Spallone V, Gurieva I, Al Kaabi J, Mankovsky B, Martinka E, Radulian G, Nguyen KT, Stirban AO, Tankova T, Varkonyi T, Freeman R, Kempler P, Boulton AJ. Screening, diagnosis and management of diabetic sensorimotor polyneuropathy in clinical practice: International expert consensus recommendations. Diabetes Res Clin Pract 2022; 186:109063. [PMID: 34547367 DOI: 10.1016/j.diabres.2021.109063] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 09/10/2021] [Accepted: 09/14/2021] [Indexed: 11/24/2022]
Abstract
Diabetic sensorimotor polyneuropathy (DSPN) affects around one third of people with diabetes and accounts for considerable morbidity, increased risk of mortality, reduced quality of life, and increased health care costs resulting particularly from neuropathic pain and foot ulcers. Painful DSPN is encountered in 13-26% of diabetes patients, while up to 50% of patients with DSPN may be asymptomatic. Unfortunately, DSPN still remains inadequately diagnosed and treated. Herein we provide international expert consensus recommendations and algorithms for screening, diagnosis, and treatment of DSPN in clinical practice derived from a Delphi process. Typical neuropathic symptoms include pain, paresthesias, and numbness particularly in the feet and calves. Clinical diagnosis of DSPN is based on neuropathic symptoms and signs (deficits). Management of DSPN includes three cornerstones: (1) lifestyle modification, optimal diabetes treatment aimed at near-normoglycemia, and multifactorial cardiovascular risk intervention, (2) pathogenetically oriented pharmacotherapy (e.g. α-lipoic acid and benfotiamine), and (3) symptomatic treatment of neuropathic pain including analgesic pharmacotherapy (antidepressants, anticonvulsants, opioids, capsaicin 8% patch and combinations, if required) and non-pharmacological options. Considering the individual risk profile, pain management should not only aim at pain relief, but also allow for improvement in quality of sleep, functionality, and general quality of life.
Collapse
Affiliation(s)
- Dan Ziegler
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
| | - Solomon Tesfaye
- Diabetes Research Department, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Vincenza Spallone
- Department of Systems Medicine, Endocrinology Section, University of Rome Tor Vergata, Rome, Italy
| | - Irina Gurieva
- Department of Endocrinology, Federal Bureau of Medical and Social Expertise, Moscow, Russia; Department of Endocrinology, Russian Medical Academy of Continuous Professional Education, Moscow, Russia
| | - Juma Al Kaabi
- Zayed Centre for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Boris Mankovsky
- Department of Diabetology, National Medical Academy for Postgraduate Education, Kiev, Ukraine
| | - Emil Martinka
- National Institute of Endocrinology and Diabetology, Lubochna, Slovak Republic; Faculty of Health Sciences University of Ss. Cyril and Methodius in Trnava, Slovak Republic
| | - Gabriela Radulian
- "N. Paulescu" National Institute of Diabetes, Nutrition and Metabolic Diseases, University of Medicine and Pharmacy "Carol Davila" Bucharest, Romania
| | - Khue Thy Nguyen
- Ho Chi Minh City University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam
| | | | - Tsvetalina Tankova
- Department of Endocrinology, Medical University - Sofia, Sofia, Bulgaria
| | - Tamás Varkonyi
- Department of Internal Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Roy Freeman
- Department of Neurology, Harvard Medical School, Boston, MA, United States
| | - Péter Kempler
- Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - Andrew Jm Boulton
- Faculty of Biology, Medicine and Health, University of Manchester and Manchester University Foundation Trust, Manchester, UK
| |
Collapse
|
|
21
|
AGA Clinical Practice Update on Management of Medically Refractory Gastroparesis: Expert Review. Clin Gastroenterol Hepatol 2022; 20:491-500. [PMID: 34757197 DOI: 10.1016/j.cgh.2021.10.038] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 10/19/2021] [Accepted: 10/24/2021] [Indexed: 02/07/2023]
Abstract
DESCRIPTION Delayed gastric emptying on objective testing defines gastroparesis, but symptoms overlap with functional dyspepsia and do not correlate well with gastric emptying delay. This review outlines a strategy for defining, diagnosing, and managing refractory gastroparesis. METHODS The Best Practice Advice statements presented here were developed from review of existing literature combined with expert opinion to provide practical advice. Because this was not a systematic review, formal rating of the quality of evidence or strength of recommendations was not performed. BEST PRACTICE ADVICE.
Collapse
|
|
22
|
Balogh M, Janjic JM, Shepherd AJ. Targeting Neuroimmune Interactions in Diabetic Neuropathy with Nanomedicine. Antioxid Redox Signal 2022; 36:122-143. [PMID: 34416821 PMCID: PMC8823248 DOI: 10.1089/ars.2021.0123] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/12/2021] [Accepted: 08/16/2021] [Indexed: 01/03/2023]
Abstract
Significance: Diabetes is a major source of neuropathy and neuropathic pain that is set to continue growing in prevalence. Diabetic peripheral neuropathy (DPN) and pain associated with diabetes are not adequately managed by current treatment regimens. Perhaps the greatest difficulty in treating DPN is the complex pathophysiology, which involves aspects of metabolic disruption and neurotrophic deficits, along with neuroimmune interactions. There is, therefore, an urgent need to pursue novel therapeutic options targeting the key cellular and molecular players. Recent Advances: To that end, cellular targeting becomes an increasingly compelling drug delivery option as our knowledge of neuroimmune interactions continues to mount. These nanomedicine-based approaches afford a potentially unparalleled specificity and longevity of drug targeting, using novel or established compounds, all while minimizing off-target effects. Critical Issues: The DPN therapeutics directly targeted at the nervous system make up the bulk of currently available treatment options. However, there are significant opportunities based on the targeting of non-neuronal cells and neuroimmune interactions in DPN. Future Directions: Nanomedicine-based agents represent an exciting opportunity for the treatment of DPN with the goals of improving the efficacy and safety profile of analgesia, as well as restoring peripheral neuroregenerative capacity. Antioxid. Redox Signal. 36, 122-143.
Collapse
Affiliation(s)
- Mihály Balogh
- Division of Internal Medicine, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jelena M. Janjic
- Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania, USA
| | - Andrew J. Shepherd
- Division of Internal Medicine, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| |
Collapse
|
|
23
|
Ramanaiah I, Sudeep HV, Shyamprasad K. Viphyllin TM, a Standardized Black Pepper Extract Exerts Antihyperglycemic Effect and Improves Sciatic Nerve Conduction in High Fat Diet/Streptozotocin-Induced Diabetic Model Rats. Diabetes Metab Syndr Obes 2022; 15:1819-1829. [PMID: 35733641 PMCID: PMC9207258 DOI: 10.2147/dmso.s366609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 05/25/2022] [Indexed: 11/23/2022] Open
Abstract
PURPOSE Research on plant-based formulations has drawn considerable attention in the management of diabetic neuropathy (DN) for having lesser side effects than the synthetic counterparts. Here, we have investigated for the first time the therapeutic effects of a standardized Piper nigrum L., (black pepper) seed extract, ViphyllinTM in mitigating hyperglycemia and neuropathic pain of type 2 diabetes model rats. METHODS Type 2 diabetes was induced in male Wistar rats using high fat diet and a single dose of streptozotocin (60 mg/kg i.p.). The diabetic rats were orally administered with Viphyllin containing not less than 30% β-caryophyllene (BCP), at 25 mg, 50 mg and 100 mg/kg/day doses for 6 weeks. Changes in body weight, fasting blood glucose (FBG), glucose tolerance, and blood biochemical parameters were measured. The nociceptive response to thermal stimulus (tail flick test) and sciatic nerve conduction velocity (NCV) were recorded at the end of study. RESULTS Viphyllin treatment markedly improved the body weight and glucose tolerance in diabetic rats. Also, the extract could significantly reduce the diabetes-induced elevation in FBG, liver and kidney indices. Further, Viphyllin dose-dependently increased the nociception latency in tail flick test compared to untreated diabetic rats (p<0.05). Viphyllin at 100 mg/kg significantly increased the NCV (44.12±1.91*** m/s vs diabetic control 25.80±1.88 m/s). The antioxidant enzyme activities in sciatic nerve tissue were considerably increased in Viphyllin-treated groups compared to diabetic control. A 6-week treatment with Viphyllin markedly reversed the pathological manifestations of diabetes in vital organs such as liver, kidney and pancreas. CONCLUSION The study concludes that Viphyllin exerts antidiabetic effects and improves nerve conduction to mitigate neuropathic pain.
Collapse
Affiliation(s)
- Illuri Ramanaiah
- Department of Preclinical Studies, R&D Center for Excellence, Vidya Herbs Pvt Ltd, Bangalore, Karnataka, 560 105, India
| | - Heggar Venkataramana Sudeep
- Department of Preclinical Studies, R&D Center for Excellence, Vidya Herbs Pvt Ltd, Bangalore, Karnataka, 560 105, India
- Correspondence: Heggar Venkataramana Sudeep, Department of Preclinical Studies, R&D Center for Excellence, Vidya Herbs Pvt Ltd, Bangalore, Karnataka, 560 105, India, Tel +91 80-42094158, Email
| | - Kodimule Shyamprasad
- Department of Preclinical Studies, R&D Center for Excellence, Vidya Herbs Pvt Ltd, Bangalore, Karnataka, 560 105, India
| |
Collapse
|
|
24
|
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.
Collapse
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
| |
Collapse
|
|
25
|
Abstract
The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
Collapse
|
|
26
|
Chen D, Fulcher J, Scott ES, Jenkins AJ. Precision Medicine Approaches for Management of Type 2 Diabetes. PRECISION MEDICINE IN DIABETES 2022:1-52. [DOI: 10.1007/978-3-030-98927-9_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
27
|
Aljassem A, Hall LM, Spickler M, Menkes DL. A Practical Approach to the Treatment of Painful Polyneuropathies. Neuromuscul Disord 2022. [DOI: 10.1016/b978-0-323-71317-7.00006-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
|
|
28
|
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.
Collapse
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
| |
Collapse
|
|
29
|
Srinivasan A, Dutta P, Bansal D, Chakrabarti A, Bhansali AK, Hota D. Efficacy and safety of low-dose naltrexone in painful diabetic neuropathy: A randomized, double-blind, active-control, crossover clinical trial. J Diabetes 2021; 13:770-778. [PMID: 34014028 DOI: 10.1111/1753-0407.13202] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 05/11/2021] [Accepted: 05/18/2021] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND There is a need for newer therapies for chronic painful diabetic neuropathy as the existing drugs have their own limitations. Clinical trials on low-dose naltrexone (1-5 mg/d) showed efficacy and safety in certain chronic painful conditions, but not in painful diabetic neuropathy. Hence the present study was planned. METHODS Sixty-seven participants with painful diabetic neuropathy were randomized to receive either 2 mg naltrexone or 10 mg amitriptyline daily following a 2-week run-in period. The participants were followed up every 2 weeks for a total of 6 weeks. Up-titration was done (to 4 mg naltrexone or 25/50 mg amitriptyline) if the pain reduction was less than 20% on the visual analog scale (VAS) during the next follow-up visit. Efficacy was assessed using the change in VAS score at the end of 6 weeks from baseline. Safety was evaluated at each follow-up visit. After 2 weeks of washout period, the participants were crossed over to receive the comparator drug for another 6 weeks with similar evaluations. RESULTS The difference (confidence interval) in the change in VAS score between groups from baseline was 1.64 (-0.92 to 4.20) in per-protocol analysis and 1.5 (-1.11 to 4.13) in intention-to-treat analysis. Eight and fifty-two adverse events were reported in the naltrexone and amitriptyline groups, respectively (P < .001). The most common adverse events were mild diarrhea with naltrexone and somnolence with amitriptyline. CONCLUSIONS Low-dose naltrexone exhibited similar efficacy and a superior safety profile compared with amitriptyline in painful diabetic neuropathy.
Collapse
Affiliation(s)
- Anand Srinivasan
- Department of Pharmacology, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Pinaki Dutta
- Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Dipika Bansal
- Department of Clinical Research, National Institute of Pharmaceutical Education and Research, SAS Nagar, India
| | - Amitava Chakrabarti
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Anil Kumar Bhansali
- Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Debasish Hota
- Department of Pharmacology, All India Institute of Medical Sciences, Bhubaneswar, India
| |
Collapse
|
|
30
|
Moon SJ, Jeon JY, Lim Y, An T, Jang SB, Kim S, Na WS, Lee SY, Kim MG. Pharmacokinetics of a New, Once-Daily, Sustained-Release Pregabalin Tablet in Healthy Male Volunteers. Clin Ther 2021; 43:1381-1391.e1. [PMID: 34256964 DOI: 10.1016/j.clinthera.2021.06.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 11/19/2022]
Abstract
PURPOSE A new sustained-release (SR) pregabalin formulation (YHD1119) designed for once-daily dosing has recently been developed to improve patient adherence. This study aimed to compare the pharmacokinetics of pregabalin SR and immediate-release (IR) formulations after multiple oral doses and to assess the effect of food on the pharmacokinetic profile of the pregabalin SR formulation after a single dose in healthy individuals. METHODS Two clinical trials were conducted: a randomized, open-label, multiple-dose, 2-treatment, 2-period crossover study to evaluate the steady-state pharmacokinetic properties of SR treatment (pregabalin SR 300 mg once daily for 3 days) and IR treatment (pregabalin IR 150 mg twice daily for 3 days) under fed conditions and a randomized, open-label, single-dose, 2-treatment, 2-period, crossover study to evaluate the effect of food intake on the pharmacokinetic properties of the pregabalin SR formulation. Plasma concentrations of pregabalin were measured using LC-MS/MS. The AUC and Cmax for pregabalin were calculated using noncompartmental method and compared between treatments in each study. FINDINGS Thirty-one individuals in the bioequivalence study and 23 in the food effect study completed the pharmacokinetic sampling. The geometric mean ratios of Cmax,ss and AUC0-τ between the SR and IR formulations were 1.1642 (90% CI, 1.1043-1.2272) and 0.9704 (90% CI, 0.9372-1.0047), respectively. The geometric mean ratios of Cmax and AUC0-last between the SR formulation in the fed state and in the fasted state were 1.6514 (90% CI, 1.3820-1.9732) and 1.7899 (90%CI, 1.4499-2.2097), respectively. IMPLICATIONS The bioavailability of the pregabalin SR 300 mg formulation is increased if taken with a high-fat meal. Once-daily pregabalin SR 300 mg is bioequivalent to twice-daily pregabalin IR 150 mg under fed conditions at steady state. The pregabalin SR formulation is expected to improve patient adherence. ClinicalTrials.gov identifiers: NCT02783183 (bioequivalence study) and NCT03191136 (food effect study).
Collapse
Affiliation(s)
- Seol Ju Moon
- Center for Clinical Pharmacology and Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju, Republic of Korea
| | - Ji-Young Jeon
- Center for Clinical Pharmacology and Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju, Republic of Korea
| | - Yeji Lim
- Clinical Development Department, R&D Division, Yuhan Corporation, Seoul, Republic of Korea
| | - Taewon An
- Clinical Development Department, R&D Division, Yuhan Corporation, Seoul, Republic of Korea
| | - Seong Bok Jang
- Clinical Development Department, R&D Division, Yuhan Corporation, Seoul, Republic of Korea
| | - Sohee Kim
- Clinical Development Department, R&D Division, Yuhan Corporation, Seoul, Republic of Korea
| | - Woon-Sook Na
- Business & New Product Development Department, R&D Division, Yuhan Corporation, Seoul, Republic of Korea
| | - Sun Young Lee
- Department of Radiation Oncology, Jeonbuk National University Medical School, Jeonju, Republic of Korea; Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Republic of Korea
| | - Min-Gul Kim
- Center for Clinical Pharmacology and Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju, Republic of Korea; Research Institute of Clinical Medicine of Jeonbuk National University, Jeonju, Republic of Korea; Department of Pharmacology, School of Medicine, Jeonbuk National University, Jeonju, Republic of Korea.
| |
Collapse
|
|
31
|
Petersen EA, Stauss TG, Scowcroft JA, Brooks ES, White JL, Sills SM, Amirdelfan K, Guirguis MN, Xu J, Yu C, Nairizi A, Patterson DG, Tsoulfas KC, Creamer MJ, Galan V, Bundschu RH, Paul CA, Mehta ND, Choi H, Sayed D, Lad SP, DiBenedetto DJ, Sethi KA, Goree JH, Bennett MT, Harrison NJ, Israel AF, Chang P, Wu PW, Gekht G, Argoff CE, Nasr CE, Taylor RS, Subbaroyan J, Gliner BE, Caraway DL, Mekhail NA. Effect of High-frequency (10-kHz) Spinal Cord Stimulation in Patients With Painful Diabetic Neuropathy: A Randomized Clinical Trial. JAMA Neurol 2021; 78:687-698. [PMID: 33818600 PMCID: PMC8022268 DOI: 10.1001/jamaneurol.2021.0538] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Question Will 10-kHz spinal cord stimulation improve pain relief for patients with painful diabetic neuropathy refractory to medical management? Findings In this randomized clinical trial including 216 patients, there was a significant benefit of 10-kHz spinal cord stimulation, with 79% of treatment responders whose underlying neurological deficits did not worsen compared with 5% of controls treated with conventional medical management. Meaning Patients with painful diabetic neuropathy with inadequate pain relief despite best available medical treatments should be considered for 10-kHz spinal cord stimulation. Importance Many patients with diabetic peripheral neuropathy experience chronic pain and inadequate relief despite best available medical treatments. Objective To determine whether 10-kHz spinal cord stimulation (SCS) improves outcomes for patients with refractory painful diabetic neuropathy (PDN). Design, Setting, and Participants The prospective, multicenter, open-label SENZA-PDN randomized clinical trial compared conventional medical management (CMM) with 10-kHz SCS plus CMM. Participants with PDN for 1 year or more refractory to gabapentinoids and at least 1 other analgesic class, lower limb pain intensity of 5 cm or more on a 10-cm visual analogue scale (VAS), body mass index (calculated as weight in kilograms divided by height in meters squared) of 45 or less, hemoglobin A1c (HbA1c) of 10% or less, daily morphine equivalents of 120 mg or less, and medically appropriate for the procedure were recruited from clinic patient populations and digital advertising. Participants were enrolled from multiple sites across the US, including academic centers and community pain clinics, between August 2017 and August 2019 with 6-month follow-up and optional crossover at 6 months. Screening 430 patients resulted in 214 who were excluded or declined participation and 216 who were randomized. At 6-month follow-up, 187 patients were evaluated. Interventions Implanted medical device delivering 10-kHz SCS. Main Outcomes and Measures The prespecified primary end point was percentage of participants with 50% pain relief or more on VAS without worsening of baseline neurological deficits at 3 months. Secondary end points were tested hierarchically, as prespecified in the analysis plan. Measures included pain VAS, neurological examination, health-related quality of life (EuroQol Five-Dimension questionnaire), and HbA1c over 6 months. Results Of 216 randomized patients, 136 (63.0%) were male, and the mean (SD) age was 60.8 (10.7) years. Additionally, the median (interquartile range) duration of diabetes and peripheral neuropathy were 10.9 (6.3-16.4) years and 5.6 (3.0-10.1) years, respectively. The primary end point assessed in the intention-to-treat population was met by 5 of 94 patients in the CMM group (5%) and 75 of 95 patients in the 10-kHz SCS plus CMM group (79%; difference, 73.6%; 95% CI, 64.2-83.0; P < .001). Infections requiring device explant occurred in 2 patients in the 10-kHz SCS plus CMM group (2%). For the CMM group, the mean pain VAS score was 7.0 cm (95% CI, 6.7-7.3) at baseline and 6.9 cm (95% CI, 6.5-7.3) at 6 months. For the 10-kHz SCS plus CMM group, the mean pain VAS score was 7.6 cm (95% CI, 7.3-7.9) at baseline and 1.7 cm (95% CI, 1.3-2.1) at 6 months. Investigators observed neurological examination improvements for 3 of 92 patients in the CMM group (3%) and 52 of 84 in the 10-kHz SCS plus CMM group (62%) at 6 months (difference, 58.6%; 95% CI, 47.6-69.6; P < .001). Conclusions and Relevance Substantial pain relief and improved health-related quality of life sustained over 6 months demonstrates 10-kHz SCS can safely and effectively treat patients with refractory PDN. Trial Registration ClincalTrials.gov Identifier: NCT03228420
Collapse
Affiliation(s)
- Erika A Petersen
- Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock
| | | | | | | | | | - Shawn M Sills
- Touchstone Interventional Pain Center, Medford, Oregon
| | | | | | - Jijun Xu
- Department of Pain Management, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Cong Yu
- Swedish Medical Center, Seattle, Washington
| | - Ali Nairizi
- Nevada Advanced Pain Specialists, Reno, Nevada
| | | | | | | | | | | | - Christopher A Paul
- Department of Anesthesiology, University of Arkansas for Medical Sciences, Little Rock
| | - Neel D Mehta
- Department of Anesthesiology, Weill Cornell Medical College, New York, New York
| | - Heejung Choi
- Department of Anesthesiology, University of Arkansas for Medical Sciences, Little Rock
| | - Dawood Sayed
- Department of Anesthesiology and Pain Medicine, University of Kansas Medical Center, Kansas City
| | - Shivanand P Lad
- Department of Neurosurgery, Duke University, Durham, North Carolina
| | | | - Khalid A Sethi
- Department of Neurosurgery, United Health Services, Johnson City, New York
| | - Johnathan H Goree
- Department of Anesthesiology, University of Arkansas for Medical Sciences, Little Rock
| | - Matthew T Bennett
- Department of Neurosurgery, United Health Services, Johnson City, New York
| | | | | | | | - Paul W Wu
- Holy Cross Hospital, Fort Lauderdale, Florida
| | - Gennady Gekht
- Coastal Orthopedics and Sports Medicine, Bradenton, Florida
| | - Charles E Argoff
- Department of Neurology, Albany Medical Center, Albany, New York
| | - Christian E Nasr
- Department of Endocrinology, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Rod S Taylor
- MRC/CSO Social and Public Health Sciences Unit, Robertson Centre for Biostatistics, Institute of Health and Well Being, University of Glasgow, Glasgow, Scotland, United Kingdom
| | | | | | | | - Nagy A Mekhail
- Department of Pain Management, Cleveland Clinic Foundation, Cleveland, Ohio
| |
Collapse
|
|
32
|
Zhao Y, Ling DY, Zhang J, Wu Q, Zhang ZW, Wang ZY. Effectiveness of acupuncture therapy for postherpetic neuralgia: an umbrella review protocol. BMJ Open 2021; 11:e043064. [PMID: 34020972 PMCID: PMC8144037 DOI: 10.1136/bmjopen-2020-043064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 05/08/2021] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION Several systematic reviews and meta-analysis indicate that acupuncture and related therapies may be a valuable adjunctive technique to pharmacological interventions for pain management of postherpetic neuralgia (PHN). However, the robustness of the results of these studies has not been evaluated. The aim of this proposed umbrella review is to provide more reliable evidence of the effectiveness of acupuncture therapy for PHN based on medical references for healthcare decision makers. METHODS AND ANALYSIS PubMed, EMBASE, The Cochrane Library, Web of Science, Chinese BioMedical Literature Database, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure and Wan fang Database will be used to retrieve reviews. The time of publication will be limited from inception to March 2021. Two reviewers will screen all retrieved articles independently to identify their eligibility and extract the data. The quality will be assessed independently by two trained reviewers using Assessment of Multiple Systematic Reviews-2 for methodological quality, Risk of Bias in Systematic Review for level of bias, Preferred Reporting Items for Systematic Reviews and Meta-Analysis for reporting quality and Grading of Recommendations Assessment, Development and Evaluation for the quality of evidence. Any disagreements will be settled by discussion or the involvement of a third reviewer. ETHICS AND DISSEMINATION The protocol of this review does not require ethical approval because the research will be based on publicly available data. The findings will be disseminated through publication in peer-reviewed international journals or presentation in academic conference. PROSPERO REGISTRATION NUMBER CRD42020173341. REPORTING CHECKLIST PRISMA-P, 2015.
Collapse
Affiliation(s)
- Yan Zhao
- Department of Pain, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Di-Yang Ling
- Department of Pain, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Juan Zhang
- Department of Pain, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Qiong Wu
- Department of Pain, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Zhen-Wu Zhang
- Department of Pain, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Zhe-Yin Wang
- Department of Pain, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| |
Collapse
|
|
33
|
Fisher AS, Lanigan MT, Upton N, Lione LA. Preclinical Neuropathic Pain Assessment; the Importance of Translatability and Bidirectional Research. Front Pharmacol 2021; 11:614990. [PMID: 33628181 PMCID: PMC7897667 DOI: 10.3389/fphar.2020.614990] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 12/10/2020] [Indexed: 02/04/2023] Open
Abstract
For patients suffering with chronic neuropathic pain the need for suitable novel therapies is imperative. Over recent years a contributing factor for the lack of development of new analgesics for neuropathic pain has been the mismatch of primary neuropathic pain assessment endpoints in preclinical vs. clinical trials. Despite continuous forward translation failures across diverse mechanisms, reflexive quantitative sensory testing remains the primary assessment endpoint for neuropathic pain and analgesia in animals. Restricting preclinical evaluation of pain and analgesia to exclusively reflexive outcomes is over simplified and can be argued not clinically relevant due to the continued lack of forward translation and failures in the clinic. The key to developing new analgesic treatments for neuropathic pain therefore lies in the development of clinically relevant endpoints that can translate preclinical animal results to human clinical trials. In this review we discuss this mismatch of primary neuropathic pain assessment endpoints, together with clinical and preclinical evidence that supports how bidirectional research is helping to validate new clinically relevant neuropathic pain assessment endpoints. Ethological behavioral endpoints such as burrowing and facial grimacing and objective measures such as electroencephalography provide improved translatability potential together with currently used quantitative sensory testing endpoints. By tailoring objective and subjective measures of neuropathic pain the translatability of new medicines for patients suffering with neuropathic pain will hopefully be improved.
Collapse
Affiliation(s)
- Amy S. Fisher
- Transpharmation Ltd., The London Bioscience Innovation Centre, London, United Kingdom
| | - Michael T. Lanigan
- Transpharmation Ltd., The London Bioscience Innovation Centre, London, United Kingdom
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
| | - Neil Upton
- Transpharmation Ltd., The London Bioscience Innovation Centre, London, United Kingdom
| | - Lisa A. Lione
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
| |
Collapse
|
|
34
|
Sasaki H, Takatsuna H, Inoue T, Matsui D, Sakoda H, Yokoyama M, Shiosakai K, Seki H, Uetake Y, Okuizumi K. A Cross-sectional Survey of Patients with Suspected Diabetic Peripheral Neuropathic Pain in Japan. Intern Med 2021; 60:357-365. [PMID: 32921690 PMCID: PMC7925283 DOI: 10.2169/internalmedicine.5512-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Objective The burden of diabetic peripheral neuropathic pain (DPNP) is poorly understood. The present study reported on the current status of DPNP in Japan, to improve our understanding of this condition among healthcare providers and inform future clinical research on its prevalence, diagnosis, and management. Methods A cross-sectional, observational study (UMIN000037023) was conducted via a web-based survey. The primary endpoints were the frequency of patients with bilateral foot symptoms, consulting a doctor, understanding DPNP, and reporting problems in daily life, as well as the treatment awareness of patients. Patients Adults ≥20 years old who were registered in the Rakuten Insight Disease Panel and receiving anti-diabetic therapy in Japan were included. Results Bilateral foot pain symptoms were reported by 1,768/7,754 (22.8%) respondents, most commonly intense numbness (13.0%). Of those with symptoms, 55.3% consulted a doctor; the most common reason for not seeking consultation was feeling that symptoms were insufficiently severe to bother their doctor (89.4%). Nearly 60% reported understanding the causes of their symptoms, with diabetes-associated neurologic deficits (58.8%) most commonly identified. About one-quarter reported daily life problems, including an inability to walk for long periods (58.3%) and feeling anxious (58.1%). Treatment awareness was reported by 18.2%; oral medications were commonly recognized (64.6%). Conclusion In Japan, 22.8% of patients with diabetes have bilateral foot pain symptoms; some experience problems in their daily life without understanding the causes of their symptoms. This supports the importance of actions to increase awareness and minimize DPNP-associated impairment of daily life in patients with diabetes.
Collapse
Affiliation(s)
- Hideyuki Sasaki
- Division of Diabetes and Metabolism, Satellite Clinic for Integrative and Anti-Aging Medicine, Wakayama Medical University, Japan
| | | | | | - Daiju Matsui
- Medical Affairs Division, Daiichi Sankyo Co., Ltd., Japan
| | - Hiroshi Sakoda
- Medical Affairs Division, Daiichi Sankyo Co., Ltd., Japan
| | | | - Kazuhito Shiosakai
- Digital Transformation Management Division, Daiichi Sankyo Co., Ltd., Japan
| | | | | | - Kaoru Okuizumi
- Medical Affairs Division, Daiichi Sankyo Co., Ltd., Japan
| |
Collapse
|
|
35
|
Yeh YC, Cappelleri JC, Marston XL, Shelbaya A. Effects of dose titration on adherence and treatment duration of pregabalin among patients with neuropathic pain: A MarketScan database study. PLoS One 2021; 16:e0242467. [PMID: 33471834 PMCID: PMC7816971 DOI: 10.1371/journal.pone.0242467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 10/25/2020] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE To examine pregabalin dose titration and its impact on treatment adherence and duration in patients with neuropathic pain (NeP). METHODS MarketScan database (2009-2014) was used to extract a cohort of incident adult pregabalin users with NeP who had at least 12 months of follow-up data. Any dose augmentation within 45 days following the first pregabalin claim was defined as dose titration. Adherence (measured by medication possession ratio/MPR) and persistence (measured as the duration of continuous treatment) were compared between the cohorts with and without dose titration. Logistic regressions and Cox proportional hazards models were used to identify the factors associated with adherence (MPR ≥ 0.8) and predictors of time to discontinuation. RESULTS Among the 5,186 patients in the analysis, only 18% of patients had dose titration. Patients who had dose titration were approximately 2.6 times as likely to be adherent (MPR ≥ 0.8) (odds ratio = 2.59, P < 0.001) than those who did not have dose titration. Kaplan-Meier analysis shows that the time to discontinuation or switch was significantly longer among patients who had dose titration (4.99 vs. 4.04 months, P = 0.009). CONCLUSIONS Dose titration was associated with improved treatment adherence and persistence among NeP patients receiving pregabalin. The findings will provide valuable evidence to increase physician awareness of dose recommendations in the prescribing information and to educate patients on the importance of titration and adherence.
Collapse
Affiliation(s)
- Yu-Chen Yeh
- Pharmerit International, Newton, MA, United States of America
- * E-mail:
| | - Joseph C. Cappelleri
- Department of Global Biometrics and Data Management, Pfizer Inc, New York, NY, United States of America
| | | | - Ahmed Shelbaya
- Department of Health Economics and Outcomes Research, Pfizer Inc, New York, NY, United States of America
- Mailman School of Public Health, Columbia University, New York, NY, United States of America
| |
Collapse
|
|
36
|
Tagami K, Matsuoka H, Ariyoshi K, Oyamada S, Hiratsuka Y, Kizawa Y, Koyama A, Inoue A. The current clinical use of adjuvant analgesics for refractory cancer pain in Japan: a nationwide cross-sectional survey. Jpn J Clin Oncol 2021; 50:1434-1441. [PMID: 32869060 DOI: 10.1093/jjco/hyaa147] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 07/22/2020] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Although adjuvant analgesics are used to treat opioid-refractory cancer pain, there is insufficient evidence to support this practice and limited data to guide the choice depending on cancer pain pathophysiology, dose titration and starting dose. This survey aimed to clarify the current use of adjuvant analgesics for treating opioid-refractory cancer pain. METHODS In this cross-sectional study, we sent an online survey questionnaire to 208 certified palliative care specialists. Primary outcomes were (i) effective pathophysiological mechanism of cancer pain and (ii) initiating doses and time period to the first response to each adjuvant analgesic therapy. RESULTS In total, 87 (42%) palliative care specialists responded. Of all patients with cancer pain, 40% of patients (median) with refractory cancer pain were prescribed adjuvant analgesics. Additionally, 94.3, 93.1 and 86.2% of palliative care specialists found dexamethasone/betamethasone effective for neuropathic pain caused by tumor-related spinal cord compression, pregabalin effective for malignant painful radiculopathy and dexamethasone/betamethasone effective for brain tumor or leptomeningeal metastases-related headache, respectively. The median starting dose of pregabalin, dexamethasone/betamethasone, lidocaine and ketamine were 75, 4, 200, and 50 mg/day, respectively, and the median time to the first response of those medications were 5, 3, 2 and 3 days, respectively. CONCLUSIONS Many palliative care specialists select adjuvant analgesics depending on the pathophysiological mechanism of cancer pain in each case. They used such adjuvant analgesics in low doses for cancer pain with short first-response periods.
Collapse
Affiliation(s)
- Keita Tagami
- Department of Palliative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiromichi Matsuoka
- Department of Psychosomatic Medicine, Kindai University Faculty of Medicine, Osakasayama, Japan.,Department of Psycho-Oncology, National Cancer Center Hospital, Tokyo, Japan
| | | | | | - Yusuke Hiratsuka
- Department of Palliative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshiyuki Kizawa
- Department of Palliative Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Atsuko Koyama
- Department of Psychosomatic Medicine, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Akira Inoue
- Department of Palliative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| |
Collapse
|
|
37
|
Abstract
The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc21-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc21-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
Collapse
|
|
38
|
Shaheen A, Alam SM, Azam F, Khan M, Ahmad Saleem S, Liaquat A, Mumtaz S. Influence of single nucleotide polymorphism of LAT1 on therapeutic response to gabapentinoids in Pakistani patients with neuropathic pain. Basic Clin Pharmacol Toxicol 2020; 128:503-510. [PMID: 33190395 DOI: 10.1111/bcpt.13534] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/02/2020] [Accepted: 11/09/2020] [Indexed: 11/30/2022]
Abstract
Gabapentinoids are substrate of L-type amino acid transporter 1 (LAT1) for distribution across the blood-brain barrier. The present study aimed to evaluate the effect of LAT1 rs4240803 genetic polymorphism on the clinical efficacy and tolerability of gabapentinoids in Pakistani patients with neuropathic pain. Three-hundred and ninety-two patients were recruited, genotyped for SNP rs4240803, and followed up for eight weeks to evaluate the clinical response to gabapentinoids in terms of pain relief, inadequate response, and the emergence of adverse events. LAT1 rs4240803 GG, GA, and AA genotype frequency were 33.42%, 47.96% and 18.62%, respectively. Out of 392 patients, 323 responded to the treatment and 17.6% discontinued either due to insufficient response or intolerable adverse events (AEs). GA genotype was more frequent in non-responder group (P ˂ 0.001). Maximum pain responders (≥50%) in combination with the lowest incidence of AEs were observed in the GG group, whereas partial responders belonged to GA genotype and with the highest frequency of somnolence (83.6%) and dizziness (69.9%). Overall, 72.5% patients with GA genotype experienced AEs (P ˂ 0.001). In conclusion, clinical outcomes of gabapentinoids are influenced by LAT1 rs4240803 polymorphism and population pharmacogenetics should be considered to evaluate the maximum potential of gabapentinoids in the management of neuropathic pain.
Collapse
Affiliation(s)
- Abida Shaheen
- Department of Pharmacology & Therapeutics, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Pakistan
| | - Syed Mahboob Alam
- Department of Pharmacology and Therapeutics, Basic Medical Sciences Institute, JPMC, Karachi, Pakistan
| | - Fahad Azam
- Department of Pharmacology & Therapeutics, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Pakistan
| | - Moosa Khan
- Department of Pharmacology & Therapeutics, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan
| | - Salman Ahmad Saleem
- Department of Pain Clinic, Shifa International Hospital, Islamabad, Pakistan
| | - Afrose Liaquat
- Department of Biochemistry, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Pakistan
| | - Sana Mumtaz
- Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Gӧttingen, Gӧttingen, Germany
| |
Collapse
|
|
39
|
A 3-way Cross-over Study of Pregabalin, Placebo, and the Histamine 3 Receptor Inverse Agonist AZD5213 in Combination With Pregabalin in Patients With Painful Diabetic Neuropathy and Good Pain-reporting Ability. Clin J Pain 2020; 37:38-42. [PMID: 33086238 DOI: 10.1097/ajp.0000000000000886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES In this study, patients with painful diabetic neuropathy were trained using an experimental pain paradigm in an attempt to enroll a subset of patients who are "pain connoisseurs" and therefore more able to discriminate between active and placebo treatments. METHODS AZD5213, a novel histamine H3 receptor inverse agonist+pregabalin, pregabalin, and placebo were then tested in a 3-period cross-over. RESULTS The study did not provide any evidence of clinical efficacy for AZD5213 when combined with pregabalin in the treatment of painful diabetic neuropathy. DISCUSSION The training of study patients in pain reporting and subsequent enrichment with good pain reporters also did not enable the robust detection of the efficacy of pregabalin relative to placebo in a small sample size. Further work is required before recommending the use of "connoisseur" patients in future neuropathic pain studies.
Collapse
|
|
40
|
UZUNER B, KETENCİ S, SALBAŞ E. Diyabetik Nöropatiye Genel Yaklaşım. ACTA MEDICA ALANYA 2020. [DOI: 10.30565/medalanya.788960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
|
|
41
|
Galan V, Scowcroft J, Chang P, Li S, Staats P, Rotte A, Subbaroyan J. 10-kHz spinal cord stimulation treatment for painful diabetic neuropathy: results from post-hoc analysis of the SENZA-PPN study. Pain Manag 2020; 10:291-300. [PMID: 32779967 DOI: 10.2217/pmt-2020-0033] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aim: Previous studies of 10 kHz spinal cord stimulation demonstrated its safety and efficacy for treatment of neuropathic pain of the trunk and/or limbs. This study analyzed data from a subset of subjects with painful diabetic neuropathy enrolled in a prospective, multicenter study of peripheral polyneuropathy with various etiologies. Materials & methods: Of the eight subjects that had permanent devices, seven attended the 12-month follow-up assessment. Results & conclusion: At 12 months, 6/7 subjects were treatment responders (≥50% pain relief) and had pain remission (visual analog scale ≤ 3.0 cm). Worsening of neurologic deficits was not reported in any subject. Instead, 5/7 subjects showed improvements in sensory testing and/or reflexes. These results support further investigation of 10 kHz spinal cord stimulation as a safe and effective treatment for intractable painful diabetic neuropathy.
Collapse
Affiliation(s)
| | | | - Paul Chang
- Georgia Pain Care, Stockbridge, GA 30281, USA
| | - Sean Li
- Premier Pain Centers, Shrewsbury, NJ 20852, USA
| | | | | | | |
Collapse
|
|
42
|
Knezevic NN, Jovanovic F, Candido KD, Knezevic I. Oral pharmacotherapeutics for the management of peripheral neuropathic pain conditions - a review of clinical trials. Expert Opin Pharmacother 2020; 21:2231-2248. [PMID: 32772737 DOI: 10.1080/14656566.2020.1801635] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Epidemiological studies have shown that 6.9-10% of people suffer from neuropathic pain, a complex painful condition which is often undertreated. Data regarding the effectiveness of treatment options for patients with neuropathic pain is inconsistent, and there is no single treatment option that shows cost-effectiveness across studies. AREAS COVERED In this narrative review, the authors present the results of different prospective, randomized controlled trials, systematic reviews and meta-analyses assessing the effects of different oral medications in the management of various peripheral neuropathic pain conditions. The authors discuss the effectiveness of commonly used oral medications such as voltage-gated calcium channels antagonists, voltage-gated sodium channel antagonists, serotonin-norepinephrine reuptake inhibitors, NMDA antagonists, and medications with other mechanisms of action. EXPERT OPINION Most of the presented medications were more effective than placebo; however, when compared to each other, none of them were significantly superior. The heterogeneity of the studies looking into different oral neuropathic conditions has been the major issue that prevents us from making stronger recommendations. There are multiple reasons including high placebo responsiveness, improperly treated underlying comorbidities (particularly anxiety and depression), and inter-patient variability. Different sensory phenotypes should also be taken into consideration when designing future clinical trials for neuropathic pain.
Collapse
Affiliation(s)
- Nebojsa Nick Knezevic
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center , Chicago, IL, US.,Department of Anesthesiology, College of Medicine, University of Illinois , Chicago, IL, US.,Department of Surgery, College of Medicine, University of Illinois , Chicago, IL, US
| | - Filip Jovanovic
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center , Chicago, IL, US
| | - Kenneth D Candido
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center , Chicago, IL, US.,Department of Anesthesiology, College of Medicine, University of Illinois , Chicago, IL, US.,Department of Surgery, College of Medicine, University of Illinois , Chicago, IL, US
| | - Ivana Knezevic
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center , Chicago, IL, US
| |
Collapse
|
|
43
|
Araki E, Goto A, Kondo T, Noda M, Noto H, Origasa H, Osawa H, Taguchi A, Tanizawa Y, Tobe K, Yoshioka N. Japanese Clinical Practice Guideline for Diabetes 2019. Diabetol Int 2020; 11:165-223. [PMID: 32802702 PMCID: PMC7387396 DOI: 10.1007/s13340-020-00439-5] [Citation(s) in RCA: 274] [Impact Index Per Article: 54.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Indexed: 01/09/2023]
Affiliation(s)
- Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Atsushi Goto
- Department of Health Data Science, Graduate School of Data Science, Yokohama City University, Yokohama, Japan
| | - Tatsuya Kondo
- Department of Diabetes, Metabolism and Endocrinology, Kumamoto University Hospital, Kumamoto, Japan
| | - Mitsuhiko Noda
- Department of Diabetes, Metabolism and Endocrinology, Ichikawa Hospital, International University of Health and Welfare, Ichikawa, Japan
| | - Hiroshi Noto
- Division of Endocrinology and Metabolism, St. Luke’s International Hospital, Tokyo, Japan
| | - Hideki Origasa
- Department of Biostatistics and Clinical Epidemiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Haruhiko Osawa
- Department of Diabetes and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan
| | - Akihiko Taguchi
- Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube, Japan
| | - Yukio Tanizawa
- Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube, Japan
| | - Kazuyuki Tobe
- First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | | |
Collapse
|
|
44
|
Araki E, Goto A, Kondo T, Noda M, Noto H, Origasa H, Osawa H, Taguchi A, Tanizawa Y, Tobe K, Yoshioka N. Japanese Clinical Practice Guideline for Diabetes 2019. J Diabetes Investig 2020; 11:1020-1076. [PMID: 33021749 PMCID: PMC7378414 DOI: 10.1111/jdi.13306] [Citation(s) in RCA: 191] [Impact Index Per Article: 38.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 05/24/2020] [Indexed: 01/09/2023] Open
Affiliation(s)
- Eiichi Araki
- Department of Metabolic MedicineFaculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Atsushi Goto
- Department of Health Data ScienceGraduate School of Data ScienceYokohama City UniversityYokohamaJapan
| | - Tatsuya Kondo
- Department of Diabetes, Metabolism and EndocrinologyKumamoto University HospitalKumamotoJapan
| | - Mitsuhiko Noda
- Department of Diabetes, Metabolism and EndocrinologyIchikawa HospitalInternational University of Health and WelfareIchikawaJapan
| | - Hiroshi Noto
- Division of Endocrinology and MetabolismSt. Luke's International HospitalTokyoJapan
| | - Hideki Origasa
- Department of Biostatistics and Clinical EpidemiologyGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
| | - Haruhiko Osawa
- Department of Diabetes and Molecular GeneticsEhime University Graduate School of MedicineToonJapan
| | - Akihiko Taguchi
- Department of Endocrinology, Metabolism, Hematological Science and TherapeuticsGraduate School of MedicineYamaguchi UniversityUbeJapan
| | - Yukio Tanizawa
- Department of Endocrinology, Metabolism, Hematological Science and TherapeuticsGraduate School of MedicineYamaguchi UniversityUbeJapan
| | - Kazuyuki Tobe
- First Department of Internal MedicineGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
| | | |
Collapse
|
|
45
|
Cragg JJ, Jutzeler CR, Grassner L, Ramer M, Bradke F, Kramer JLK. Beneficial "Pharmaceutical Pleiotropy" of Gabapentinoids in Spinal Cord Injury: A Case for Refining Standard-of-Care. Neurorehabil Neural Repair 2020; 34:686-689. [PMID: 32508248 DOI: 10.1177/1545968320931516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Spinal cord injury results in devastating neurological deficits accompanied by lifelong disability and significant economic burden. While the development of novel compounds or cell-based interventions for spinal cord injury is unquestionably worthwhile, a complementary approach examines current standards of care and the degree to which these can be optimized to benefit long-term neurological function. Numerous classes of drugs, already in use in the acute phase of spinal cord injury, are intriguing because they (1) readily cross the blood-spinal cord barrier to modulate activity in the central nervous system and (2) are administered during a window of time in which neuroprotection, and even some repair, are feasible. Here, we review a rare case of convergent lines of evidence from both preclinical and human studies to support the early administration of a class of drug (ie, gabapentinoids) to both foster motor recovery and reduce the severity of neuropathic pain.
Collapse
Affiliation(s)
- Jacquelyn J Cragg
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | | | - Lukas Grassner
- Paracelsus Medical University, Salzburg, Austria.,Medical University Innsbruck, Innsbruck, Austria
| | - Matt Ramer
- International Collaboration on Repair Discoveries (ICORD), Vancouver, British Columbia, Canada
| | - Frank Bradke
- German Centre for Neurodegenerative Disease (DZNE), Bonn, Germany
| | - John L K Kramer
- International Collaboration on Repair Discoveries (ICORD), Vancouver, British Columbia, Canada
| |
Collapse
|
|
46
|
The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An Update on Unipolar Nonpsychotic Depression. Harv Rev Psychiatry 2020; 27:33-52. [PMID: 30614886 DOI: 10.1097/hrp.0000000000000197] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND The Psychopharmacology Algorithm Project at the Harvard South Shore Program presents evidence-based recommendations considering efficacy, tolerability, safety, and cost. Two previous algorithms for unipolar nonpsychotic depression were published in 1993 and 1998. New studies over the last 20 years suggest that another update is needed. METHODS The references reviewed for the previous algorithms were reevaluated, and a new literature search was conducted to identify studies that would either support or alter the previous recommendations. Other guidelines and algorithms were consulted. We considered exceptions to the main algorithm, as for pregnant women and patients with anxious distress, mixed features, or common medical and psychiatric comorbidities. SUMMARY For inpatients with severe melancholic depression and acute safety concerns, electroconvulsive therapy (or ketamine if ECT refused or ineffective) may be the first-line treatment. In the absence of an urgent indication, we recommend trialing venlafaxine, mirtazapine, or a tricyclic antidepressant. These may be augmented if necessary with lithium or T3 (triiodothyronine). For inpatients with non-melancholic depression and most depressed outpatients, sertraline, escitalopram, and bupropion are reasonable first choices. If no response, the prescriber (in collaboration with the patient) has many choices for the second trial in this algorithm because there is no clear preference based on evidence, and there are many individual patient considerations to take into account. If no response to the second medication trial, the patient is considered to have a medication treatment-resistant depression. If the patient meets criteria for the atypical features specifier, a monoamine oxidase inhibitor could be considered. If not, reconsider (for the third trial) some of the same options suggested for the second trial. Some other choices can also considered at this stage. If the patient has comorbidities such as chronic pain, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, or posttraumatic stress disorder, the depression could be secondary; evidence-based treatments for those disorders would then be recommended.
Collapse
|
|
47
|
Shinozuka T, Kobayashi H, Suzuki S, Tanaka K, Karanjule N, Hayashi N, Tsuda T, Tokumaru E, Inoue M, Ueda K, Kimoto H, Domon Y, Takahashi S, Kubota K, Yokoyama T, Shimizugawa A, Koishi R, Fujiwara C, Asano D, Sakakura T, Takasuna K, Abe Y, Watanabe T, Kitano Y. Discovery of DS-1971a, a Potent, Selective NaV1.7 Inhibitor. J Med Chem 2020; 63:10204-10220. [DOI: 10.1021/acs.jmedchem.0c00259] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Tsuyoshi Shinozuka
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Hiroyuki Kobayashi
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Sayaka Suzuki
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Kyosuke Tanaka
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Narayan Karanjule
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Noriyuki Hayashi
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Toshifumi Tsuda
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Eri Tokumaru
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Masahiro Inoue
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Kiyono Ueda
- R&D Division, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan
| | - Hiroko Kimoto
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Yuki Domon
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Sakiko Takahashi
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Kazufumi Kubota
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Tomihisa Yokoyama
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Akiko Shimizugawa
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Ryuta Koishi
- R&D Division, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan
| | - Chie Fujiwara
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Daigo Asano
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Tomoko Sakakura
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Kiyoshi Takasuna
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Yasuyuki Abe
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Toshiyuki Watanabe
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Yutaka Kitano
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| |
Collapse
|
|
48
|
Schmierer PA, Tünsmeyer J, Tipold A, Hartnack-Wilhelm S, Lesczuk P, Kästner SBR. Randomized controlled trial of pregabalin for analgesia after surgical treatment of intervertebral disc disease in dogs. Vet Surg 2020; 49:905-913. [PMID: 32329092 DOI: 10.1111/vsu.13411] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 01/15/2020] [Accepted: 02/25/2020] [Indexed: 12/01/2022]
Abstract
OBJECTIVE To assess the effect of perioperative pregabalin on pain behavior in dogs after intervertebral disc surgery. STUDY DESIGN Prospective, randomized, controlled clinical trial with a blinded observer. ANIMALS Forty-six client-owned dogs undergoing intervertebral disc surgery. METHODS Dogs were randomly assigned to two groups, with the placebo group receiving opioids alone and the pregabalin group receiving opioids plus pregabalin. Opioid analgesia consisted of 0.6 mg/kg l-methadone given intravenously at anesthetic induction, followed by 0.2 mg/kg given at 8, 16, and 24 hours after extubation and fentanyl patches applied at the end of surgery. Pregabalin was given orally (4 mg/kg) 1 hour before anesthesia, followed by postoperative treatment three times per day (4 mg/kg) for 5 days. The outcome measures were the treatment-group differences in peri-incisional mechanical sensitivity and Glasgow Composite Measure Pain Scale (CMPS-SF) assessed during the first 5 postoperative days. Pregabalin serum concentrations were measured after 24, 72, and 120 hours. RESULTS Pregabalin reduced pain levels in the treatment group by a mean of 2.5 CMPS-SF units (95% confidence interval [CI] = -3.19 to -1.83, P < .001) compared with the control group during the study period. Pregabalin increased the mechanical nociceptive threshold by a mean of 6.89 N per day (95% CI = 1.87-11.92, P < .001) and of 7.52 N per day (95% CI = 2.29-12.77, P < .001) during the study period, depending on location. Mean levels of serum pregabalin were 5.1, 4.71, and 3.68 μg/mL at 24, 72, and 120 hours postoperatively, respectively. CONCLUSION Postoperative signs of pain after surgical treatment of intervertebral disc herniation (IVDH) were reduced when dogs received perioperative pregabalin rather than opioids alone. CLINICAL SIGNIFICANCE Perioperative pregabalin reduces postoperative pain after surgical treatment of IVDH.
Collapse
Affiliation(s)
- Philipp A Schmierer
- Clinic for Small Animal Surgery, Vetsuisse Faculty University of Zurich, Zurich, Switzerland.,Tierklinik Posthausen, Posthausen, Germany
| | - Julia Tünsmeyer
- Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany
| | - Andrea Tipold
- Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany
| | - Sonja Hartnack-Wilhelm
- Department for Biostatistics, Vetsuisse Faculty University of Zurich, Zurich, Switzerland
| | - Piotr Lesczuk
- Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.,Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Bialystok, Poland.,Department of Biochemical Diagnostics, University Hospital of Bialystok, Bialystok, Poland
| | - Sabine B R Kästner
- Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany
| |
Collapse
|
|
49
|
Alles SRA, Cain SM, Snutch TP. Pregabalin as a Pain Therapeutic: Beyond Calcium Channels. Front Cell Neurosci 2020; 14:83. [PMID: 32351366 PMCID: PMC7174704 DOI: 10.3389/fncel.2020.00083] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 03/20/2020] [Indexed: 12/12/2022] Open
Abstract
Initially developed to generate new treatments for epilepsy, gabapentin, and pregabalin (“gabapentinoids”) were engineered to mimic the action of GABA and to modulate GABA metabolism. Rather than their intended pharmacological action on GABA neurotransmission, instead, they exhibit a high affinity for the α2δ-1 and α2δ-2 subunits of voltage-activated calcium channels, wherein binding of gabapentinoids inhibits cellular calcium influx and attenuates neurotransmission. Despite a lack of activity on GABA levels, gabapentin and pregabalin are effective at suppressing seizures and subsequently approved as a new class of antiepileptic therapy for partial-onset epilepsy. Through the same hypothesized molecular mechanism and by controlling neuronal hyperexcitability, gabapentinoids demonstrate clear efficacy in pain management, which has arguably been their most extensively prescribed application to date. In this review, we focus on pregabalin as a second-generation gabapentinoid widely employed in the treatment of a variety of pain conditions. We also discuss the wider functional roles of α2δ subunits and the contributions that pregabalin might play in affecting physiological and pathophysiological processes.
Collapse
Affiliation(s)
- Sascha R A Alles
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Djavad Mowafaghian Center for Brain Health, University of British Columbia, Vancouver, BC, Canada.,Department of Anesthesiology and Critical Care Medicine, University of New Mexico School of Medicine, Albuquerque, NM, United States
| | - Stuart M Cain
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Djavad Mowafaghian Center for Brain Health, University of British Columbia, Vancouver, BC, Canada
| | - Terrance P Snutch
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Djavad Mowafaghian Center for Brain Health, University of British Columbia, Vancouver, BC, Canada
| |
Collapse
|
|
50
|
|