Systematic review on combination pharmacotherapy: methodological rigor but no pharmacology (2022)

Drug combinations are commonly used in medicine, eg, in the management of high blood pressure. What comes to pain, the most common combination is paracetamol (acetaminophen) or a nonsteroidal anti-inflammatory drug (NSAID) administered with an opioid. The basic principle is to combine drugs that have distinctly different mechanisms of action. The aim is to achieve improved analgesia with less adverse effects. In pharmacology, the increased efficacy of combining drug A with drug B is tested with a so-called isobologram analysis or the contour method.5 The mathematical analysis requires that dose–response curves are established for both drugs A and B and for their combination. The result will show whether combining A and B produces an effect that equals the sum of the effects of the monotherapies A + B (an additive effect) or is more than that (a synergistic effect). The effect can also be less than the sum of A + B (antagonistic effect). Establishing isobolograms in clinical trials is usually not feasible. These different effects of drug combinations can be due to pharmacodynamic effects (eg, inhibition of the cyclooxygenase enzymes and activation of opioid receptors). It can also be due to pharmacokinetic effects by induction or inhibition of the drug-metabolizing cytochrome P (CYP) enzymes. When an NSAID is combined with an opioid, there are rarely pharmacokinetic interactions. The main effect of NSAIDs is in the periphery, whereas the main effects of opioids occur in the central nervous system (CNS), resulting in an additive or even synergistic effect. The efficacy of drugs used to manage neuropathic pain (NP) is inadequate. The number-to-treat values for at least 50% pain relief vary between 3 and 9 depending on the drug and type of pain.3 This is reflected in a recent report showing that more than half of the patients receive 2 or more analgesics including antidepressants, anticonvulsants, and opioids.4 Compared with the combination of an NSAID and an opioid, the combinations of the drugs that are used to manage NP are more problematic. Most of these drugs are metabolized by CYP enzymes, leading to possible pharmacokinetic interactions. Also, all orally administered drugs used to manage NP affect the CNS, increasing the load of CNS-mediated adverse effects. In this issue of PAIN,1 a renowned research group updated a 2012 Cochrane Collaboration systematic review and meta-analysis that examined the efficacy and safety of combinations of drugs used in the management of NP.2 The analysis included double-blind randomized controlled trials evaluating combinations of 2 or more drugs compared with placebo and/or at least 1 monotherapy in adults with NP. Forty studies, 19 more than in the 2012 review, with 4741 participants, were included. The main results were that the meta-analyses failed to demonstrate superiority for either efficacy or adverse effect profiles for opioid–antidepressant, opioid–gabapentinoid, or gabapentinoid–antidepressant combinations over monotherapies. The studies were heterogenous, and it was concluded that further research is needed to identify clinical settings and specific combinations that safely provide added benefit. The methods of the included studies are meticulously reported according to the Cochrane and PRISMA guidelines. The same applies to the validated outcomes for analgesic efficacy and adverse effects. The main outcome for analgesic efficacy was set to at least 30% reduction of pain intensity. The search was extensive including non–English-language trial publications and completed pharmaceutical industry trials through ClinicalTrials.gov and the ISRCTN Registry. The amount of work invested into this study has been huge because the search resulted in 2566 results of which 2462 underwent full-text screening and 80 publications full-text review. As 61 studies were excluded, 19 new studies were included in the analyses. The extracted data and the extensive statistical analyses are shown in several large tables and figures. The results consist of a long list reporting the numbers of different drug combinations, numbers of patients in each, statistics for pain intensity differences, and adverse effects. The most common combinations were opioids, antidepressants, and gabapentinoids. Interestingly, also topical combinations of amitriptyline/ketamine cream or baclofen and amitriptyline gel were included in the review. Other exotic combinations included glycerol nitrate spray and oral sodium valproate. Cochrane-type systematic reviews do not discuss the hypotheses behind the studies being analyzed or reasons for patients (not) responding to the therapy. Some discussion about the role of pharmacokinetic drug interactions would have been useful. Very few clinical studies have measured analgesic drug concentrations that may significantly vary because of pharmacogenetic and pharmacokinetic reasons. Codeine is a prime example. Also, the combined blood concentrations of amitriptyline and its active metabolite nortriptyline can vary ten-fold after the same dose.6 Concentration measurements would be particularly essential when drug combinations are studied. The main focus of Cochrane-type systematic reviews and meta-analyses is in the rigorous identification and evaluation of all available evidence using standard methods to minimize errors and bias. Too often the conclusion is that the outcome data were incomplete, and because of the small number of study participants and heterogeneity, no conclusions could be drawn. The reader may feel disheartened after having read an extensive review, which did not provide any answers. The authors are not to be blamed. They did their work meticulously. The problem is in the methods and aims of Cochrane-type systematic reviews that ignore the individual patient and the substance, pain medicine, pharmacology, and psychology. All analyses are processed by the same protocol. The clinician would, however, like to know whether some patients actually benefitted from the combinations of analgesics and the reasons for some patients responding, whereas others do not. Systematic reviews and meta-analyses have brought rigor to the design of clinical trials, but they have not advanced our understanding of the “real substance” in pain research. It is time to reconsider the research methodology that the current evidence is based upon and start asking clinically relevant questions such as why patients may respond differently to the same treatment. Although meticulously performed systematic reviews continue to be valuable, major advances could be made by using individual patient data in analyses and designing large single case studies with enough relevant phenotype data and new outcomes. Conflict of interest statement E. Kalso has served in the advisory boards of Pfizer and Orion Pharma, not related to this commentary. E. Kalso has received a lecture fee from GSK, not related to this work.