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Combination Therapy for Neuropathic Pain
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 (NP) occurs as a direct consequence of an injury or disease that affects the somatosensory system . The prevalence of NP in the population varies from 6.9% to 10%, depending on the tool used for its diagnosis , and it negatively affects quality of life, impacting daily activities, such as sleeping and walking, and family and social interactions. . 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 . Pharmacological therapy remains an important component of NP management . 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 .
The treatment of NP is effective in less than 50% of patients and is also associated with significant adverse drug effects . 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) . 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 ; more elaborated efficacy reports with an increased goal (i.e., the use of 30% to 50% pain reduction as outcome measures) ; and the contribution of other factors for higher levels of placebo response in NP RCTs .
Therefore, CT is becoming more and more popular among clinicians , 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 ; (2) targeting more than one NP mechanism simultaneously with CT could be a better approach than targeting a single mechanism with a single drug  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 , the 9-year gap since the last published Cochrane review (the previous one was published 7 years earlier, in 2005, by Gilron et al. ), 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 .
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 . 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 ; a different drug combination (opioid plus pregabalin (PGB) plus duloxetine (DXT) was tested in one RCT in NP in cancer patients ; one tested a combination of DXT and PGB against both of them on monotherapy in painful diabetic neuropathy (PDN) ; another compared a drug combination of dextromethorphan and quinidine against a placebo, again in PDN ; and capsaicin 8% dermal patch (CP8) in combination with systemic NP medications was evaluated in another RCT in postherpetic neuralgia (PHN) . 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.
|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 ||Central neuropathic pain in patients with multiple sclerosis||DB;
|14||THC/CBD + concomitant analgesic medication||32.4/30 mg||oromucosal (spay) + oral||167 (41)||Placebo||oromucosal (spray) + oral||172 (156)|
|Shaibani 2012 ||Diabetic neuropathic pain||DB;
|Irving 2012 ||Postherpetic neuralgia||DB;
|12||Capsaicin + concomitant neuropathic medication||640 µg/cm2||topical (skin) + oral||597 (544)||Placebo||topical (skin) + oral||530 (480)|
|Tesfaye 2013 ||Diabetic neuropathic pain in patients who are non-responders to duloxetine or pregabalin||DB;
|8||Duloxetine + Pregabalin||60 + 300 mg||oral||170 (141)||Duloxetine
|Holbech 2015 ||Painful polyneuropathy||DB;
|5||Imipramine + Pregabalin||75 + 300 mg||oral||18 (15)–16 (15) –15 (12)–16 (14)||Placebo
|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 ||Neuropathic pain in cancer patients who are non-responders to opioid–pregabalin||DB; PARALLEL||1,5
|Duloxetine + Opioid–Pregabalin||40 mg + ?—300 mg||oral||35 (34)||Placebo +
|?- 300 mg||oral||35 (33)|
Five studies reported the number of patients with a ≥50% pain reduction , and in other studies, this number was deduced from the figures . Most of these studies also reported the number of patients with ≥30% pain reduction, except for two studies . 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 .
We assessed the issue of other bias as being high risk in studies where the follow-up was shorter than twelve weeks  and/or where the study had fewer than 50 participants per arm or period of treatment in parallel or crossover studies, respectively .
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.
This entry is adapted from 10.3390/jcm10163533
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