Combination Drug Therapy for Pain: A Conundrum

Modern pharmacotherapies for pain often combine multiple drugs for added beneficial effects; however, there also can be unfavorable consequences of such therapy. According to a new critical review, clinical evidence supporting multidrug therapies is sparse, which may pose a challenging dilemma, or conundrum, for prescribers.

In the February 2011 edition of the Journal of Pain Jianren Mao, from Harvard Medical School, and colleagues observe that managing debilitating chronic pain can be a daunting responsibility for general healthcare providers and specialists — including neurologists, rheumatologists, oncologists, gynecologists, and pain practitioners [Mao et al. 2011]. As a vital part of multidisciplinary approaches, medications are often prescribed in combinations, which they refer to as “combination drug therapy (CDT).”

By “combination” they are referring to two or more drugs prescribed either individually or in a pre-formulated combination product. This is sometimes also known as “polypharmacy” and, in certain cases, use of one or more of the drugs may be for an unapproved (ie, “off label”) application. In practice today, CDT often appears to be driven more by empiricism — that is, trial and error clinical experience — than by definitive evidence from extensive, high-quality clinical research trials.

According to their review, Mao et al. believe that CDT may be both necessary and justified in many cases. For one thing, co-prescribed agents may help to maximize therapeutic effectiveness while minimizing harmful side effects. For example, two compounds may have additive effects (eg, NSAID + opioid) or supra-additive, synergistic, effects (eg, gabapentin + opioid), providing enhanced analgesia at lower dosages of each agent, which may reduce adverse effect potential of each. In other cases, one of the drugs may be included specifically to counter side effects of another in the combination (eg, diclofenac + misoprostol).

The authors describe several approaches to CDT: (1) combining drugs from the same drug class that differ in their onset and duration of action, such as pairing an immediate-release with an extended-release opioid analgesic, (2) combining two or more drugs from different classes, such as an opioid with a tricyclic antidepressant, and (3) combining drugs delivered through different routes, such as a topical agent (lidocaine) with an oral agent (gabapentin). In certain cases, fixed-ratio drug combinations are available, often comprising two drugs from different classes; for example, certain short-acting opioid analgesics are combined with either ibuprofen or acetaminophen (eg, oxycodone-ibuprofen, tramadol-acetaminophen, etc.).

The choice of drugs in combination must take into account the type of chronic pain condition, the underlying mechanisms generating the pain, and individual factors (such as metabolism). Depending on the constellation of pain mechanisms involved, and potential changes at the cellular and system level, multiple drugs may be used in combination to attack a range of therapeutic targets. For example, treatment of neuropathic pain might include sodium-channel blockers, calcium-channel blockers, serotonin-norepinephrine reuptake inhibitors, and agents to attenuate microglial activation (eg, minocycline), as well as traditional analgesics (eg, opioids, NSAIDs, acetaminophen).

However, the authors caution that the effectiveness of CDT for chronic pain remains uncertain in many cases due to a lack of clinical trials directly comparing single-drug therapy with CDT, and the lack of standards for conducting such trials if they are undertaken. To date, several consensus guidelines for single drug therapy in pain management have been published; yet, only a limited number of clinical studies on CDT have been reported and their external validity requires further confirmation.

Consequently, Mao et al. stress an essential truth that is often overlooked: “…adding more medications into a treatment regimen does not always lead to better pain relief and/or functional recovery, but it surely increases the cost and possibly side effects of drug therapy.” Also, it is important that adjunctive modalities of chronic pain management are considered, such as cognitive behavioral therapy, physical therapies, rehabilitation, and others. Along with that, pain relief may not be the only outcome measure of importance; multiple outcomes, including overall function and adverse effects should be taken into account.

While one benefit of CDT may be reduced adverse effects, there also is potential for increased deleterious effects in some cases. For example, unique adverse effects from drug combinations may include (a) serotonin syndrome from a combination of tramadol and a selective serotonin and/or norepinephrine reuptake inhibitor, (b) worsening sedation and mental status changes from a tricyclic antidepressant + opioid analgesic combination, and (c) liver toxicity with some agents.

For any combination, several additional questions need resolution via established clinical research approaches, such as: Will the drug combination have a synergistic or an additive interaction? Will the impact of CDT on pain relief and functional recovery be sustainable over time? What is the possible influence of metabolic drug-drug interactions on the outcome of CDT? Are there special concerns of CDT in the elderly or other populations of patients?

The authors conclude that, although CDT can be beneficial for certain chronic pain conditions, considerably more data are needed to provide guidelines for both the most appropriate choice of drug combinations and the most appropriate clinical circumstances. Given the current absence of data demonstrating increased efficacy of various drug combinations, along with concerns about potential deleterious consequences of CDT, it is essential that more clinical trials are initiated to provide necessary guidance for the most effective utilization of this treatment strategy.

Postscript: With recent actions by the U.S. FDA to reduce acetaminophen dosage amounts in prescription combination analgesics containing acetaminophen [discussed in UPDATE here], some institutions are considering discontinuing use of all such combination products. This might not be the most prudent course of action, as the additive effects of acetaminophen plus the other agent — at lower doses of each than might be otherwise needed to provide comparable analgesia — would be sacrificed. For equivalent pain relief it might be necessary to either prescribe a greater dose of the other ingredient (eg, opioid) used individually or substitute a different non-opioid agent in the mix (eg, NSAID), with attendant potential for increased side effects. Either way, this highlights both the complexities and importance of combination drug therapies, or CDT, for pain.

REFERENCE: Mao J, Gold MS, Backonja M. Combination Drug Therapy for Chronic Pain: A Call for More Clinical Studies. J Pain. 2011(Feb);12(2):157-166 [abstract here]