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Serrano-Afonso, A. Combination Therapy for Neuropathic Pain. Encyclopedia. Available online: https://encyclopedia.pub/entry/15188 (accessed on 27 July 2024).
Serrano-Afonso A. Combination Therapy for Neuropathic Pain. Encyclopedia. Available at: https://encyclopedia.pub/entry/15188. Accessed July 27, 2024.
Serrano-Afonso, Ancor. "Combination Therapy for Neuropathic Pain" Encyclopedia, https://encyclopedia.pub/entry/15188 (accessed July 27, 2024).
Serrano-Afonso, A. (2021, October 20). Combination Therapy for Neuropathic Pain. In Encyclopedia. https://encyclopedia.pub/entry/15188
Serrano-Afonso, Ancor. "Combination Therapy for Neuropathic Pain." Encyclopedia. Web. 20 October, 2021.
Combination Therapy for Neuropathic Pain
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This entry is adapted from the peer-reviewed paper 10.3390/jcm10163533

We evaluated the efficacy, tolerability, and safety of double-blinded randomized controlled trials involving only adult participants and comparing combination therapy (CT: ≥2 drugs) with a placebo and/or at least one other comparator with an NP indication. The primary outcome assessed was the proportion of participants reporting ≥50% pain reductions from baseline. The secondary outcome assessed was the proportion of drop-outs due to treatment-emergent adverse events.

neuropathic pain combination therapy pharmacotherapy randomized control trial

1. Introduction

Neuropathic pain (NP) occurs as a direct consequence of an injury or disease that affects the somatosensory system [1]. The prevalence of NP in the population varies from 6.9% to 10%, depending on the tool used for its diagnosis [2], and it negatively affects quality of life, impacting daily activities, such as sleeping and walking, and family and social interactions. [3]. Patients with uncontrolled pain continuously suffer heavy individual and societal burdens, which could make them believe that chronic pain is inevitable and untreatable, especially for those who are not responding to standard measures. A considerable number of patients do not achieve a satisfactory pain relief or improvements in their quality of life with currently available drugs [4]. Pharmacological therapy remains an important component of NP management [5][6]. However, more than a decade has passed since the market release of the last drug suggested for NP treatment, according to international guidelines. 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 [7][8].

The treatment of NP is effective in less than 50% of patients and is also associated with significant adverse drug effects [9]. In addition, decreases in drug effect have been reported across all drug classes, with a progressive increase in the number needed to treat (NNT) in randomized control trials (RCTs) [10]. The reason for this increase in NNT numbers is not well known. This is probably due to a combination of different causes: more complex trial designs required by regulatory agencies, such as the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA), with larger sample sizes, longer study periods, better randomization and blinding reports, and intention-to-treat (ITT) analysis [11][12][13]; more elaborated efficacy reports with an increased goal (i.e., the use of 30% to 50% pain reduction as outcome measures) [10][14]; and the contribution of other factors for higher levels of placebo response in NP RCTs [15].

Therefore, CT is becoming more and more popular among clinicians [16][17][18][19], and its rationale lies on two theories: (1) a phenotypic profile-guided treatment improves symptomatic control (i.e., different clinical signs and symptoms are suggested to reflect different underlying mechanisms) and offers the possibility of an individualized mechanism-based treatment approach for different somatosensory patterns [20][21][22]; (2) targeting more than one NP mechanism simultaneously with CT could be a better approach than targeting a single mechanism with a single drug [23][24] since it may allow lower doses of individual drugs (due to a synergistic effect) and improve their safety/tolerability profile.

Considering the decreasing estimates in drug effect in NP RCTs [10], the 9-year gap since the last published Cochrane review (the previous one was published 7 years earlier, in 2005, by Gilron et al. [25]), and the absence of a consensus among clinicians regarding when to start CT and which drugs to combine, we thought it was appropriate to perform a new and independent systematic review.

2. Development and Findings

We applied the following criteria when selecting studies for the qualitative analysis.

We only included studies involving adult participants 18 years and older with a diagnosis of NP.

We searched for the following types of bias in all of the studies included for qualitative analysis: random sequence generation and allocation concealment (selection bias), blinding, incomplete outcome data, selective reporting, and other potential sources of bias. We graded all selected studies for quality per the Cochrane Risk of Bias tool [26].

For those studies with more than one active treatment group, we divided the control group among the active treatment arms to allow comparison between them.

We identified 16 studies that fulfilled the inclusion criteria for this review: RCTs, double-blinded, and a comparison of combinations of two or more drugs with a placebo and/or at least one other comparator for the treatment of NP [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. Among them, only six provided data on the primary outcome (proportion of participants reporting ≥50% or ≥30% pain reductions from baseline), either by direct reporting or by deduction through study figures or graphs (data from such studies can be seen in Table 1 ). In total, 1243 participants were included in the study drugs groups vs. 928 were included in the control groups: one RCT evaluated the combination of cannabinoids delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray and the existing treatment regimen for central neuropathic pain (CNP) in patients with multiple sclerosis [40]; a different drug combination (opioid plus pregabalin (PGB) plus duloxetine (DXT) was tested in one RCT in NP in cancer patients [29][37]; one tested a combination of DXT and PGB against both of them on monotherapy in painful diabetic neuropathy (PDN) [39]; another compared a drug combination of dextromethorphan and quinidine against a placebo, again in PDN [42]; and capsaicin 8% dermal patch (CP8) in combination with systemic NP medications was evaluated in another RCT in postherpetic neuralgia (PHN) [41]. Likewise, these studies also provided data on the secondary outcomes: (i) the proportion of participants dropping out of the study due to treatment-emergent adverse effects and (ii) the proportion of participants reporting each specific adverse effect (i.e., sedation and dizziness) with moderate or greater severity.

Table 1. Data from the selected studies.
Name Pain Condition RCT Treatment Duration (Weeks) Combination Target Ceiling Dose or MTD per Day Route Sample Size RD (CS) Control Target Ceiling Dose or MTD per Day Route Sample Size RD (CS)
Langford 2013 [40] Central neuropathic pain in patients with multiple sclerosis DB;
PARALLEL		 14 THC/CBD + concomitant analgesic medication 32.4/30 mg oromucosal (spay) + oral 167 (41) Placebo   oromucosal (spray) + oral 172 (156)
Shaibani 2012 [42] Diabetic neuropathic pain DB;
PARALLEL		 13 DMQ 90/60 mg
60/60 mg		 oral
oral		 131 (79)
125 (74)		 Placebo   oral 123 (89)
Irving 2012 [41] Postherpetic neuralgia DB;
PARALLEL		 12 Capsaicin + concomitant neuropathic medication 640 µg/cm2 topical (skin) + oral 597 (544) Placebo   topical (skin) + oral 530 (480)
Tesfaye 2013 [39] Diabetic neuropathic pain in patients who are non-responders to duloxetine or pregabalin DB;
PARALLEL		 8 Duloxetine + Pregabalin 60 + 300 mg oral 170 (141) Duloxetine
Pregabalin		 120 mg
600 mg		 oral
oral		 74 (?)
99 (?)
Holbech 2015 [35] Painful polyneuropathy DB;
CROSSOVER		 5 Imipramine + Pregabalin 75 + 300 mg oral 18 (15)–16 (15) –15 (12)–16 (14) Placebo
Imipramine
Pregabalin		 75 mg
300 mg;		 oral
oral
oral		 19 (18)–16 (15)–15 (13) 12 (11)
18 (17)–17 (14)–14 (14)–12 (12)
18 (15)–16 (14)–14 (14)–13 (13)
Matsuoka 2019 [29] Neuropathic pain in cancer patients who are non-responders to opioid–pregabalin DB; PARALLEL 1,5
(10 days)		 Duloxetine + Opioid–Pregabalin 40 mg + ?—300 mg oral 35 (34) Placebo +
Opioid- Pregabalin		 ?- 300 mg oral 35 (33)
RCT: randomized controlled trial; MTD: maximum tolerated dose; RD (CS): randomized (completed study); DB: double-blind; THC/CBD: tetrahydrocannabinol/cannabidiol; DMQ: dextromethorphan + quinidine; ?: data not available.

Five studies reported the number of patients with a ≥50% pain reduction [35][39][40][41][42], and in other studies, this number was deduced from the figures [29]. Most of these studies also reported the number of patients with ≥30% pain reduction, except for two studies [35][40]. One study described the proportion of patients reporting ≥50% pain reductions and ≥30% pain reductions, but these proportions were assessed using a secondary analysis producing the overall percentage from all treatment groups on a three-branch crossover study. The number of participants could not be calculated from this percentage or from the diagram of participants included and withdrawn from the study [34]. 

Only one study [37] was not blinded. Among the other studies, although all of them claimed to be blinded, 5 out of 15 studies [27][32][33][38][42] did not describe the blinding procedure.

We assessed the issue of other bias as being high risk in studies where the follow-up was shorter than twelve weeks [29][35][39] and/or where the study had fewer than 50 participants per arm or period of treatment in parallel or crossover studies, respectively [29][35].

3. Conclusions

Neuropathic pain treatment continues to be an unmet medical need, as patients keep reporting inadequate pain relief. Clinicians continue to have problems dealing with how to face pharmacological strategy when first-line treatment fails. CT has been a practice adopted for many years for which the evidence is not solid. Efforts have been made to achieve better-quality evidence, but the quality has not improved over the years. Guidelines for neuropathic pain should attempt to make recommendations about CT research, prioritizing which combinations to analyze over others, so that the search for better evidence can take steps forward.

References

  1. Treede, R.-D.; Jensen, T.S.; Campbell, J.N.; Cruccu, G.; Dostrovsky, J.O.; Griffin, J.W.; Hansson, P.; Hughes, R.; Nurmikko, T.; Serra, J. Neuropathic pain: Redefinition and a grading system for clinical and research purposes. Neurology 2007, 70, 1630–1635.
  2. Van Hecke, O.; Austin, S.K.; Khan, R.A.; Smith, B.; Torrance, N. Neuropathic pain in the general population: A systematic review of epidemiological studies. Pain 2014, 155, 654–662.
  3. O’Brien, T.; Breivik, H. The impact of chronic pain—European patients’ perspective over 12 months. Scand. J. Pain 2012, 3, 23–29.
  4. Binder, A.; Baron, R. The Pharmacological Therapy of Chronic Neuropathic Pain. Dtsch. Aerzteblatt Online 2016, 113, 616–625.
  5. Bates, D.; Schultheis, B.C.; Hanes, M.C.; Jolly, S.M.; Chakravarthy, K.V.; Deer, T.R.; Levy, R.M.; Hunter, C.W. A Comprehensive Algorithm for Management of Neuropathic Pain. Pain Med. 2019, 20, S2–S12.
  6. Pickering, G.; Marcoux, M.; Chapiro, S.; David, L.; Rat, P.; Michel, M.; Bertrand, I.; Voute, M.; Wary, B. An Algorithm for Neuropathic Pain Management in Older People. Drugs Aging 2016, 33, 575–583.
  7. Cruccu, G.; Sommer, C.; Anand, P.; Attal, N.; Baron, R.; Garcia-Larrea, L.; Haanpaa, M.; Jensen, T.S.; Serra, J.; Treede, R.-D. EFNS guidelines on neuropathic pain assessment: Revised 2009. Eur. J. Neurol. 2010, 17, 1010–1018.
  8. Finnerup, N.; Attal, N.; Haroutounian, S.; McNicol, E.; Baron, R.; Dworkin, R.H.; Gilron, I.; Haanpää, M.; Hansson, P.; Jensen, T.S.; et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015, 14, 162–173.
  9. Finnerup, N.B.; Haroutounian, S.; Kamerman, P.; Baron, R.; Bennett, D.; Bouhassira, D.; Cruccu, G.; Freeman, R.; Hansson, P.; Nurmikko, T.; et al. Neuropathic pain: An updated grading system for research and clinical practice. Pain 2016, 157, 1599–1606.
  10. Finnerup, N.B.; Haroutounian, S.; Baron, R.; Dworkin, R.H.; Gilron, I.; Haanpaa, M.; Jensen, T.S.; Kamerman, P.R.; McNicol, E.; Moore, A.; et al. Neuropathic pain clinical trials: Factors associated with decreases in estimated drug efficacy. Pain 2018, 159, 2339–2346.
  11. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for Industry Analgesic Indications: Developing Drug and Biological Products. DRAFT GUIDANCE. Feb-ruary 2014. 5150dft.doc. Available online: https://www.fdanews.com/ext/resources/files/02/02-05-14-Analgesic.pdf (accessed on 6 May 2021).
  12. Committee for Medicinal Products for Human Use (CHMP). Guideline on Clinical Medicinal Products Intended for the Treatment of Neuropathic Pain. London, 24 January 2007. Doc. Ref. CPMP/EWP/252/03 Rev. 1. Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-medicinal-products-intended-treatment-neuropathic-pain_en.pdf (accessed on 1 August 2021).
  13. Committee for Medicinal Products for Human Use (CHMP). Guideline on the Clinical Development of Medicinal Products Intended for the Treatment of Pain. 15 December 2016 EMA/CHMP/970057/201. Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-development-medicinal-products-intended-treatment-pain-first-version_en.pdf (accessed on 1 August 2021).
  14. Gewandter, J.S.; McDermott, M.P.; Mbowe, O.; Edwards, R.R.; Katz, N.P.; Turk, D.C.; Dworkin, R.H. Navigating trials of personalized pain treatments: We’re going to need a bigger boat. Pain 2019, 160, 1235–1239.
  15. Arakawa, A.; Kaneko, M.; Narukawa, M. An Investigation of Factors Contributing to Higher Levels of Placebo Response in Clinical Trials in Neuropathic Pain: A Systematic Review and Meta-Analysis. Clin. Drug Investig. 2015, 35, 67–81.
  16. Moisset, X.; Bouhassira, D.; Couturier, J.A.; Alchaar, H.; Conradi, S.; Delmotte, M.; Lanteri-Minet, M.; Lefaucheur, J.; Mick, G.; Piano, V.; et al. Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations. Rev. Neurol. 2020, 176, 325–352.
  17. Mu, A.; Weinberg, E.; Moulin, D.E.; Clarke, H. Pharmacologic management of chronic neuropathic pain: Review of the Canadian Pain Society consensus statement. Can. Fam. Phys. 2017, 63, 844–852.
  18. De Oliveira, R.A.A.; Baptista, A.F.; Sá, K.N.; Barbosa, L.M.; Nascimento, O.J.M.D.; Listik, C.; Moisset, X.; Teixeira, M.J.; De Andrade, D.C. Pharmacological treatment of central neuropathic pain: Consensus of the Brazilian Academy of Neurology. Arq. De Neuro-Psiquiatr. 2020, 78, 741–752.
  19. Holbech, J.V.; Jung, A.; Jonsson, T.; Wanning, M.; Bredahl, C.; Bach, F. Combination treatment of neuropathic pain: Danish expert recommendations based on a Delphi process. J. Pain Res. 2017, 10, 1467–1475.
  20. Baron, R.; Gierthmühlen, J. Neuropathic Pain. Semin. Neurol. 2016, 36, 462–468.
  21. Forstenpointner, J.; Otto, J.; Baron, R. Individualized neuropathic pain therapy based on phenotyping: Are we there yet? Pain 2018, 159, 569–575.
  22. Baron, R.; Maier, C.; Attal, N.; Binder, A.; Bouhassira, D.; Cruccu, G.; Finnerup, N.B.; Haanpää, M.; Hansson, P.; Hüllemann, P.; et al. Peripheral neuropathic pain: A mechanism-related organizing principle based on sensory profiles. Pain 2017, 158, 261–272.
  23. Gilron, I.; Jensen, T.S.; Dickenson, A.H. Combination pharmacotherapy for management of chronic pain: From bench to bedside. Lancet Neurol. 2013, 12, 1084–1095.
  24. Eisenberg, E.; Suzan, E. Drug Combinations in the Treatment of Neuropathic Pain. Curr. Pain Headache Rep. 2014, 18, 1–8.
  25. Gilron, I.; Max, M.B. Combination pharmacotherapy for neuropathic pain: Current evidence and future directions. Expert Rev. Neurother. 2005, 5, 823–830.
  26. Sterne, J.A.C.; Savović, J.; Page, M.J.; Elbers, R.G.; Blencowe, N.S.; Boutron, I.; Cates, C.J.; Cheng, H.-Y.; Corbett, M.S.; Eldridge, S.M.; et al. RoB 2: A revised tool for assessing risk of bias in random-ised trials. BMJ 2019, 366, l4898.
  27. Singh, R.; Rao, H.K.; Singh, T.G. Comparison of safety and efficacy of pregabalin, duloxetine and their combination with epalrestat in diabetic neuropathy: A prospective, doubleblind, randomized, controlled trial. J. Appl. Pharm. Sci. 2021, 11 (Suppl. 1), 71–79.
  28. Pickering, G.; Pereira, B.; Morel, V.; Corriger, A.; Giron, F.; Marcaillou, F.; Bidar-Beauvallot, A.; Chandeze, E.; Lambert, C.; Bernard, L.; et al. Ketamine and Magnesium for Refractory Neuropathic Pain. Anesthesiology 2020, 133, 154–164.
  29. Matsuoka, H.; Iwase, S.; Miyaji, T.; Kawaguchi, T.; Ariyoshi, K.; Oyamada, S.; Satomi, E.; Ishiki, H.; Hasuo, H.; Sakuma, H.; et al. Additive Duloxetine for Cancer-Related Neuropathic Pain Nonresponsive or Intolerant to Opioid-Pregabalin Therapy: A Randomized Controlled Trial (JORTC-PAL08). J. Pain Symptom Manag. 2019, 58, 645–653.
  30. Dou, Z.; Jiang, Z.; Zhong, J. Efficacy and safety of pregabalin in patients with neuropathic cancer pain undergoing morphine therapy. Asia-Pac. J. Clin. Oncol. 2017, 13, e57–e64.
  31. Rigo, F.K.; Trevisan, G.; Godoy, M.C.; Rossato, M.F.; Dalmolin, G.D.; Silva, M.A.; Menezes, M.S.; Caumo, W.; Ferreira, J. Management of Neuropathic Chronic Pain with Methadone Combined with Ketamine: A Randomized, Double Blind, Active-Controlled Clinical Trial. Pain Phys. 2017, 20, 207–215.
  32. Kim, H.-J.; Kim, J.H.; Park, Y.S.; Suk, K.-S.; Lee, J.H.; Park, M.S.; Moon, S.-H. Comparative study of the efficacy of limaprost and pregabalin as single agents and in combination for the treatment of lumbar spinal stenosis: A prospective, double-blind, randomized controlled non-inferiority trial. Spine J. 2016, 16, 756–763.
  33. Baron, R.; Martin-Mola, E.; Müller, M.; Dubois, C.; Falke, D.; Steigerwald, I. Effectiveness and Safety of Tapentadol Prolonged Release (PR) Versus a Combination of Tapentadol PR and Pregabalin for the Management of Severe, Chronic Low Back Pain With a Neuropathic Component: A Randomized, Double-blind, Phase 3b Study. Pain Pract. 2014, 15, 455–470.
  34. Gilron, I.; Tu, D.; Holden, R.R.; Jackson, A.; DuMerton-Shore, D. Combination of morphine with nortriptyline for neuropathic pain. Pain 2015, 156, 1440–1448.
  35. Holbech, J.V.; Bach, F.; Finnerup, N.; Brosen, K.; Jensen, T.S.; Sindrup, S. Imipramine and pregabalin combination for painful polyneuropathy. Pain 2015, 156, 958–966.
  36. Turcotte, D.; Doupe, M.; Torabi, M.; Gomori, A.; Ethans, K.; Esfahani, F.; Galloway, K.; Namaka, M. Nabilone as an Adjunctive to Gabapentin for Multiple Sclerosis-Induced Neuropathic Pain: A Randomized Controlled Trial. Pain Med. 2015, 16, 149–159.
  37. Garassino, M.C.; Piva, S.; La Verde, N.; Spagnoletti, I.; Iorno, V.; Carbone, C.; Febbraro, A.; Bianchi, A.; Bramati, A.; Moretti, A.; et al. Randomised Phase II Trial (NCT00637975) Evaluating Activity and Toxicity of Two Different Escalating Strategies for Pregabalin and Oxycodone Combination Therapy for Neuropathic Pain in Cancer Patients. PLoS ONE 2013, 8, e59981.
  38. Harrison, T.; Miyahara, S.; Lee, A.; Evans, S.; Bastow, B.; Simpson, D.; Gilron, I.; Dworkin, R.; Daar, E.S.; Wieclaw, L.; et al. Experience and Challenges Presented by a Multicenter Crossover Study of Combination Analgesic Therapy for the Treatment of Painful HIV-Associated Polyneuropathies. Pain Med. 2013, 14, 1039–1047.
  39. Tesfaye, S.; Wilhelm, S.; Lledo, A.; Schacht, A.; Tölle, T.; Bouhassira, D.; Cruccu, G.; Skljarevski, V.; Freynhagen, R. Duloxetine and pregabalin: High-dose monotherapy or their combination? The “COMBO-DN study”—A multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain 2013, 154, 2616–2625.
  40. Langford, R.M.; Mares, J.; Novotna, A.; Vachova, M.; Novakova, I.; Notcutt, W.; Ratcliffe, S. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. J. Neurol. 2013, 260, 984–997.
  41. Irving, G.A.; Backonja, M.; Rauck, R.; Webster, L.R.; Tobias, J.; Vanhove, G.F. NGX-4010, a Capsaicin 8% Dermal Patch, Administered Alone or in Combination With Systemic Neuropathic Pain Medications, Reduces Pain in Patients With Postherpetic Neuralgia. Clin. J. Pain 2012, 28, 101–107.
  42. Shaibani, A.I.; Pope, L.E.; Thisted, R.; Hepner, A. Efficacy and Safety of Dextromethorphan/Quinidine at Two Dosage Levels for Diabetic Neuropathic Pain: A Double-Blind, Placebo-Controlled, Multicenter Study. Pain Med. 2012, 13, 243–254.
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