Management of neuropathic pain in combination

Neuropathic pain

1. Pregabalin + Duloxetine : Combination Therapy for Neuropathic Pain Dr Nikhil Dongre Associate Consultant of Neurology Alexis Multi- speciality Hospital Nagpur MBBS(KEM Mumbai),MD General Medicine ( RNT Udaipur) DM Neurology ( SGPGI Lucknow ),DrNB Neurology Ex Asst Professor SGPGI Lucknow,Ex Asst Professor GSVM Kanpur

2. Neuropathic pain “The International Association for the Study of Pain (IASP) defines neuropathic pain as pain caused by a lesion or disease of the somatosensory nervous system” The somatosensory system is the network of neural structures in the brain and body that produce the perception of touch, as well as temperature, body position (proprioception), and pain. Jensen TS, et al. A new definition of neuropathic pain. Pain. 2011;152(10):2204–5.

3. Neuropathic pain More frequent in women (8% versus 5.7% in men) Common in patients >50 years of age (8.9% versus 5.6% in those <49 years of age) Most commonly affects the lower back and lower limbs, neck and upper limbs The prevalence of neuropathic pain in the general population has been estimated at 6.9–10.0%

4. Clinical symptoms of Neuropathic pain

5. Classification Neuropathic pain Central Central post-stroke pain syndrome Spinal cord injury Pain from multiple sclerosis Peripheral Painful diabetic neuropathy Fibromyalgia Post-herpetic neuralgia Trigeminal neuralgia Postoperative pain Tumor infiltration neuropathy Phantom limb pain Neuropathic pain syndromes can be divided into two general categories: Those that are consequences of a peripheral lesion or disease Those that are consequences of a central lesion or disease.

6. Classification of neuropathic pain and neuroanatomical distribution of pain and sensory abnormalities.

7. Epidemiology of Neuropathic pain of various etiologies Painful diabetic polyneuropathy (DPN) (estimated prevalence: 14–26% ) Post-herpetic neuralgia (PHN) (estimated prevalence: 8–10% ) Neuropathic pain related to surgery (estimated prevalence: 10–50% depending on the surgery) Central pain in Multiple sclerosis (estimated prevalence: 20–30% ) Spinal cord injury neuropathic pain (estimated prevalence: 30– 40%) Central post-stroke pain (estimated prevalence: 5–11% ) Cancer related neuropathic pain (estimated prevalence: 17–19% ) Rev Neurol (Paris). 2019 Jan-Feb;175(1-2):16-25

8. Burden of Neuropathic pain

9. Management of Neuropathic pain Treatment options Pharmacological Physical Therapy Behavioral Therapy Neuromodulation Interventional Approaches Realistic therapy goals for neuropathic pain are: Pain reduction by ≥30% Improvement of sleep quality Improvement of quality of life Preservation of social activity and relationships Maintaining the ability to work Improved functionality

10. Pharmacotherapy for neuropathic pain

11. Treatment approach to neuropathic pain in Indian setup Indian J Pain 2018;32:132-44.

12. Unmet needs The four main reasons that treatments for neuropathic pain fail are: Inadequate diagnosis and a lack of appreciation of the mechanisms involved Insufficient management of comorbid conditions (Anxiety, depression and sleep disorder) Incorrect understanding or selection of treatment options Use of inappropriate outcomes measures Issues related to Efficacy Current management strategies fail to achieve adequate or satisfactory pain relief in a high proportion of patients. Issues related to safety profile These drugs also have severe dose-dependent side effects and tolerability issues that often lead to discontinuation of high-dose monotherapies. J Pain Symptom Manage. 2003 May;25(5 Suppl ):S12-7.

13. Rationale for Combination therapy in Neuropathic Pain Clinical guidelines recommend starting treatment with monotherapy and placing combination treatment (CT) in a second tier for patients who do not respond to monotherapy or switching. The goals of combination therapy in the management of neuropathic pain include: Adequate pain relief Reduction in adverse effects Improvement of treatment compliance Restoration of functional status. Combination therapy allows targeting more than one NP mechanism simultaneously and thus it could be a better approach than targeting a single mechanism with a single drug. Combination therapy also allow use of lower doses of individual drugs (due to a synergistic effect) and improve their safety/tolerability profile. CNS Drugs. 2011 Dec 1;25(12):1023-34. J Clin Med. 2021 Aug 11;10(16):3533.

14. Rationale for FDC of Pregabalin and Duloxetine FDC of pregabalin and Duloxetine allows use of 2 drugs with different mechanism of action thus targeting multiple NP mechanism. The combination may have additive effect resulting in enhanced pain relief compared to the use of either drug alone. It also allows use of lower doses of individual drugs and thus may improve safety profile and patient compliance Some of the experts concluded that in their clinical experience, moderate-dose pregabalin/gabapentin and SNRI combination therapy results in sufficient pain relief and fewer side effects compared with monotherapy.

15. Introducing… Pregabalin and Duloxetine (Delayed release pellets) Capsules 50/20, 75/20, 75/30 mg

16. FDC of Pregabalin and Duloxetine Composition: Each gelatin capsule of Pregabalin and Duloxetine (delayed release pellets) contains 50/20 mg or 75/20 mg or 75/30 mg Indication: for the treatment of neuropathic pain Dosing: once capsule to be taken twice or thrice daily

17. State of art formulation

18. Pregabalin Pregabalin is the first drug to receive US-FDA approval for Painful diabetic neuropathy Post-herpetic neuralgia Fibromyalgia Neuropathic pain associated with spinal cord injury Pregabalin has demonstrated anticonvulsant, analgesic, and anxiolytic properties Pregabalin is rapidly absorbed and exhibits linear pharmacokinetics after oral administration. The lack of hepatic metabolism and lack of interaction with cytochrome P-450 isoenzymes explain the minimal drug interactions with pregabalin. Am J Health Syst Pharm. 2007;64(14):1475-1482.

19. Pregabalin – Mechanism of action Pregabalin reduce the release of excitatory neurotransmitter by binding to the α2-δ protein subunit of voltage-gated calcium channels. Decreased release of glutamate and sensory neuropeptides (substance P and CGRP) at synapse Low glutamate levels in synapse are unable to activate NMDA receptors This reduces neuronal firing and thus provides significant pain relief. Curr Neuropharmacol . 2014 Jan; 12(1): 44–56.

20. Pregabalin – Compared to Gabapentin AAN guidelines for DPN - Level A evidence while Gabapentin has Level B evidence Pregabalin is also remarkably more potent than Gabapentin Dose titration – maximal dose reached in days vs Gabapentin which takes weeks (long titration period) Better PK profile than Gabapentin Greater oral bioavailability than Gabapentin (>90% vs 40 – 60%) Absorption is linear across a wide range of doses while absorption of Gabapentin is saturable . Less time to reach Tmax than Gabapentin (1 hr vs 2-3 hrs ) Antacids decrease the oral bioavailability of Gabapentin by 20–30%, but do not affect the absorption of pregabalin Clin Drug Invest 2009; 29 (3): 203-213

21. Pregabalin – Compared to Gabapentin Clin Drug Invest 2009; 29 (3): 203-213

22. Duloxetine Duloxetine hydrochloride is a dual reuptake inhibitor of serotonin and norepinephrine It has been licensed for Major depressive disorder (MDD) Generalized anxiety disorder (GAD) Diabetic peripheral neuropathic pain (DPNP) Fibromyalgia Chronic musculoskeletal pain.

23. Duloxetine – Mechanism of action Duloxetine is thought to restore the levels of 5-HT and noradrenaline in the synaptic cleft by binding at their re-uptake transporters preventing the re-uptake and subsequent degradation of 5-HT and noradrenaline. Increased levels of Serotonin and noradrenaline in the synapse

24. Duloxetine – Mechanism of action Duloxetine is thought to restore the levels of 5-HT and noradrenaline in the synaptic cleft by binding at their re-uptake transporters preventing the re-uptake and subsequent degradation of 5-HT and noradrenaline. Increased levels of Serotonin and noradrenaline in the synapse Serotonin and noradrenaline plays an important role in modulating descending pain inhibition pathways in CNS. Analgesic effect of duloxetine is related to augmentation of 5-HT and NE mediated inhibitory pain pathways resulting in the decreased perception of pain

25. Pregabalin has been shown to be a well tolerated, effective treatment for neuropathic pain associated with DPN or PHN, with average time to reduction in pain of 2 days. A total of 4527 patients from 16 placebo-controlled trials of pregabalin for treatment of painful DPN or PHN were included in the analysis Findings demonstrate that statistically significant and sustained improvement in sleep occurs rapidly ( within 1 day for some patients ) in response to treatment with pregabalin. American Journal of Therapeutics 22, 257–268 (2015)

26. Annals of Physical and Rehabilitation Medicine 52 (2009) 124–141 Pregabalin is the only drug with 1 - Level of Evidence A Grade of Recommendation for SCI pain Level of evidence and grade of commendation for the pharmacological treatments evaluated in SCI pain (based on the classification of the French Authority of Health, HAS).

27. Efficacy of pregabalin and gabapentin for neuropathic pain in spinal-cord injury Spinal-cord injury (SCI) is a leading cause of neuropathic pain (NP). A systematic review was done to determine the efficacy of pregabalin and gabapentin in the treatment of NP in SCI. Five studies were eligible for inclusion. Two of them studied PB and three GP. Both GP and PB appear to be efficacious for NP in SCI. The literature data suggest that Pregabalin is more efficacious than Gabapentin in many important variables for NP in SCI. Eur J Clin Pharmacol (2008) 64:851–858

28. Clinical evidence Duloxetine data

29. Comparative Evaluation of Duloxetine Versus Amitriptyline in Patients with Diabetic Peripheral Neuropathic Pain In this randomized, double-blind, cross-over, active-control trial, 58 patients received amitriptyline and duloxetine orally once daily at bedtime, each for 6 weeks with optional dose up titration fortnightly. Single-blinded placebo washout was given for 2 weeks between the two treatments and a single-blinded placebo run-out phase of 4 weeks was given at the end of the treatment period. Pain relief was measured by the patient’s global assessment of efficacy, using a visual analog scale (0–100) as a primary end point, and overall improvement and adverse events were assessed as secondary outcome measures

30. Comparative Evaluation of Duloxetine Versus Amitriptyline in Patients with Diabetic Peripheral Neuropathic Pain There was a significant improvement in pain with both treatments compared with their baseline values (P < 0.001 for both). Of the reported adverse events, dry mouth was significantly more common with amitriptyline than duloxetine (55 vs. 24%; P<0.01). Numerically, more patients preferred duloxetine . Dose escalation with amitriptyline was limited by its TEAEs (especially dry mouth).

31. Int J Clin Pract, September 2015, 69, 9, 957–966. A phase 3, multicenter, randomised, double-blind, parallel, placebo-controlled, 12-week trial of the treatment of DPNP with duloxetine (60 mg once daily) 203 patients were assigned to duloxetine 60 mg once daily and 202 patients were assigned to placebo The primary efficacy measure was the reduction in pain severity from baseline to 12 weeks, as measured by the weekly mean of 24-h average pain ratings recorded in the patient’s diary.

32. Change from baseline in weekly mean of 24-h average pain severity Duloxetine-treated patients showed significantly greater pain relief compared with placebo-treated patients beginning 1 week after randomization and continuing through the 12-week treatment phase Int J Clin Pract, September 2015, 69, 9, 957–966.

33. Categorical analysis of patient responses on the Patient Global Impression of Improvement scale More duloxetine-treated patients (47.2%) responded with ‘ much better ’ than placebo-treated patients

34. Health outcomes measures Improvement in the BPI-Interference average score was significantly greater in the duloxetine-treated vs. the placebo-treated group ( p = 0.001 ). Significant improvements for patients treated with duloxetine (compared with placebo) were also shown in the SDS total score ( p = 0.020 ). Brief Pain Inventory-Modified Short Form-Severity (BPI-Severity) Sheehan Disability Scale (SDS) Int J Clin Pract, September 2015, 69, 9, 957–966.

35. To investigate the long-term efficacy and safety of duloxetine in the patients with diabetic neuropathic pain 258 patients were randomized (1:1) to 40 mg/day or 60 mg/day duloxetine Pain (Brief Pain Inventory severity and interference), Quality of life (Patient’s Global Impression of Improvement), Safety (adverse events, vital signs, metabolic measures) J Diabetes Investig 2016; 7: 100–108

36. All scores decreased significantly from the start of the long-term study (P < 0.0001 for all scores) J Diabetes Investig 2016; 7: 100–108

37. J Diabetes Investig 2016; 7: 100–108 The BPI severity – average pain score decreased from the first week of the study and continued to decline throughout the study period Improvements in quality of life increased during the long-term study

38. Safety Findings show that duloxetine has an acceptable safety and tolerability profile in adults with DNP, consistent with findings from long-term studies There were no significant or remarkable differences between dose groups in the efficacy or safety of duloxetine in the present long-term study J Diabetes Investig 2016; 7: 100–108

39. Safety and Tolerability Most common adverse events Pregabalin: Most common adverse reactions (greater than or equal to 5% and twice placebo) in adults are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and thinking abnormal (primarily difficulty with concentration/attention) Duloxetine: Most common adverse reactions (≥5% and at least twice the incidence of placebo-treated patients) in adults are nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis. Contraindications Pregabalin: Known hypersensitivity to pregabalin or any of its components Duloxetine: Concomitant use of an MAOI antidepressant with duloxetine is contraindicated Use of duloxetine within 14 days of stopping an MAOI antidepressant is contraindicated In linezolid- or intravenous methylene blue-treated patients, initiation of duloxetine is contraindicated

40. Drug interactions Pregabalin: Since pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (less than 2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that pregabalin is unlikely to be involved in significant pharmacokinetic drug interactions Duloxetine: Potent inhibitors of CYP1A2 should be avoided Potent inhibitors of CYP2D6 may increase duloxetine concentrations Duloxetine is a moderate inhibitor of CYP2D6

41. Treatment recommendations for neuropathic pain from various international guidelines NeupSIG = The Neuropathic Pain Special Interest Group EFNS = The European Federation of the Neurological Societies CPS=Canadian Pain Society NICE = National Institute of Health and Care Excellence Lancet Neurol 2015;14:162‑73. Eur J Neurol 2010;17:1113‑e88. Pain Res Manag 2014;19:328‑35. Available from: https://www.nice.org . uk /guidance/cg173 Both Pregabalin and Duloxetine are recommended as first therapy

42. Key Highlights Neuropathic pain is caused by a lesion or disease of the somatosensory system, including peripheral neurons and central neurons, and affects 7–10% of the general population. Current management strategies for neuropathic pain fail to achieve adequate or satisfactory pain relief in a high proportion of patients. Side effects and tolerability issues that often lead to discontinuation of high-dose monotherapies. Clinical guidelines recommend use of combination treatment (CT) for patients who do not respond to monotherapy or switching. Combination therapy allows targeting more than one NP mechanism and use of lower doses of individual drugs

43. Key Highlights Both Pregabalin and Duloxetine are first line therapies for management of neuropathic pain. In patients with partial response to monotherapy, using combination of Pregabalin and Duloxetine may have additive effect resulting in enhanced pain relief and fewer side effects compared with monotherapy. In DPNP patients, the responder rates were higher in the combination group compared to monotherapy In fibromyalgia patients, combination of pregabalin and duloxetine improves multiple clinical outcomes ( pain relief, physical function and overall quality of life) vs monotherapy Combination therapy of pregabalin and duloxetine is more effective than monotherapy in treatment of fibromyalgia.