Chapter 21
Combined pharmacotherapy for chronic pain management

Ian Gilron¹, Troels Staehelin Jensen^2,3, & Anthony H. Dickenson⁴

¹Departments of Anesthesiology & Perioperative Medicine and Biomedical & Molecular Sciences, Queen’s University, Kingston, Ontario, Canada

²Danish Pain Research Center, Aarhus University, Aarhus, Denmark

³Department of Neurology, Aarhus University Hospital, Aarhus, Denmark

⁴Department of Neuroscience, Physiology and Pharmacology, Division of Biosciences, University College, London, United Kingdom

Introduction

Chronic pain affects 20‐30% of the population in developed countries, [1, 2] imposes an adverse financial impact greater than that of cancer, diabetes and cardiovascular disease, [3] and contributes substantially to the global burden of disease [4]. Pharmacotherapy with a variety of drug classes continues to be an important component of multimodal, multidisciplinary chronic pain management [5, 6]. However, individual drugs often have limited utility due to incomplete analgesic efficacy and/or dose‐limiting adverse effects [7]. In addressing these limitations, it has been hypothesized that combining two (or more) different analgesic drugs could provide additional benefit by: 1) increasing efficacy through concurrent targeting of multiple analgesic sites and/or mechanisms; and/or 2) reducing adverse effects – particularly if additive analgesic effects can facilitate dose reduction of each drug in the combination [8], In other therapeutic areas, rational combination therapy has long been used in various conditions such as asthma [9], cancer [10] and hypertension [11], but only more recently so for pain management. Although combining two or more analgesic drugs continues to be a common practice in clinical pain management [12, 13], the evidence base supporting this practice is somewhat limited and only starting to emerge [14–16] and experts have recommended further research on the safety and efficacy of combination drug therapy for chronic pain [5, 17]. In this chapter, we review preclinical, clinical and other information regarding the rationale, practice and future directions of combination pharmacotherapy for chronic noncancer pain with the exclusion of headache, which is discussed elsewhere [18].

Current status of drug therapy for chronic pain

Various different drug classes have been recommended for the treatment of chronic noncancer pain – as first‐ or second‐line therapy depending on pain condition – including acetaminophen, nonsteroidal anti‐inflammatory drugs, antidepressant drugs, anticonvulsant drugs and tramadol (Table 21.1). Strong opioids have been recommended as third‐line therapy for neuropathic pain [5] and low back pain [19] only, but are otherwise not recommended for fibromyalgia or osteoarthritis; separate guidelines for opioids in chronic pain have also been disseminated [20, 21]. Chronic pain conditions often feature sensory hyperexcitability that manifests as hyperalgesia (increased response to noxious stimuli) and allodynia (pain produced by normally non‐noxious stimuli) [22]. This sensory hyperexcitability may be reduced by antidepressants, anticonvulsants and opioids [23] through actions on calcium channels, sodium channels and uptake mechanisms for monoamines or G‐protein coupled membrane receptors expressed in neurons that are widespread throughout the nervous system such as peripheral, spinal, brainstem, limbic and cortical structures. In addition to potential analgesic and antihyperalgesic effects, adverse effects of most of these drugs may be experienced and include sedation, dizziness and memory or cognitive problems. Therefore, additive or synergistic analgesic interactions of two different drugs administered in combination could result in fewer adverse effects if the analgesic interaction allows for optimal pain relief at lower drug doses that are associated with fewer side effects.

Table 21.1 Recommendations for pharmacological treatment of chronic noncancer pain

Pain Condition	First‐line or Second‐line Recommendation	Weaker recommendation	Not recommended
Neuropathic pain^[5]	1^st line: – tricyclic antidepressants – SNRI antidepressants –gabapentin/pregabalin	2^nd line: – tramadol^* 3^rd line: – strong opioids^*	– cannabinoids – valproate – levetiracetam – mexiletine
Osteoarthritis of the hand, hip or knee^[6]	Strong recommendation: – oral NSAIDs	Conditional recommendation: – acetaminophen – tramadol^* – duloxetine	– chondroitin – glucosamine – ‘non‐tramadol’ opioids
Fibromyalgia^*^[49]		Weak recommendation: – amitriptyline – duloxetine – milnacipran – tramadol – pregabalin – cyclobenzaprine	‐ opioids
Low back pain^[19]	1^st line: – oral NSAIDs 2^nd line: – tramadol – duloxetine	– opioids (only if 1^st/2^nd line treatments failed)^*

SNRI – serotonin‐norepinephrine reuptake inhibitor; NSAID – nonsteroidal anti‐inflammatory drug

^* Despite weak recommendations for tramadol or strong opioids shown in these previously published guidelines, some experts have more recently advocated against tramadol and strong opioids for general use in chronic noncancer pain.

Clinical rationale for analgesic combinations

As one of several treatment modalities for chronic pain, drug therapy is often ineffective in a substantial proportion of patients and only partially effective in another patient subgroup. Identifying specific drug combinations that provide better combined effectiveness versus monotherapy could increase the overall effectiveness of drug therapy for chronic pain. Since multiple, concurrent neural mechanisms of pain generation and transmission are often involved in chronic pain, combining two or more different drug classes to concurrently target these underlying mechanisms provides a rational approach to improve the effectiveness of drug therapy. In a clinical setting where a patient reports only partial benefit in response to a single analgesic drug, prescribers often then pursue “add‐on” polypharmacy (e.g. see [25]) with the intention of attaining additional pain relief.

In principle, adding a second analgesic – “drug B” – to an only partially effective first treatment – “drug A” – could provide: A) better analgesia by adding a second drug with complementary actions, or a treatment that in some other way potentiates “drug A”; B) fewer side effects with “drug B” that directly antagonizes adverse effects of “drug A” [e.g. opioid plus central nervous system (CNS) stimulant] or with an “A+B” combination that provides maximal analgesia at lower drug doses such that overall side effects are reduced; or C) treatment of other pain‐related symptoms (e.g. sleep disturbance, depression, anxiety), such as the nighttime addition of a sedating antidepressant drug to a nonsteroidal anti‐inflammatory. Also, since multiple different pain mechanisms may be important within an individual patient (e.g., inflammatory and neuropathic sources of low back pain), another rationale for combination therapy could include the concurrent targeting of multiple pain mechanisms, e.g. both an anti‐inflammatory and an anti‐neuropathic treatment.

However, despite the observation that polypharmacy for chronic pain is a common practice, evidence shows that – for some combinations and in some clinical conditions – combination therapy does not always confer added benefit and in some cases may simply increase adverse effects. For example, in one trial of participants with lumbar radiculopathy, monotherapy with nortriptyline or morphine failed to demonstrate efficacy and combining the two provided no added benefit [26]. In another trial, ketamine, but not calcitonin, demonstrated efficacy for phantom limb pain but their combination was no better than ketamine monotherapy [27]. In a trial of participants suffering from postherpetic neuralgia, combining the phenothiazine, fluphenazine, to amitriptyline provided no added analgesia compared to amitriptyline alone and, furthermore, sedation was increased during combination therapy [28]. Thus, these are examples pointing to the need for expanded research on combination pharmacotherapy, so as to guide rational, evidence‐based identification of specific analgesic combinations that safely provide improved outcomes versus monotherapy. Recent research efforts have sought to identify predictors of a favorable treatment response to combination treatment. For example, one recent genetic study identified a polymorphism (rs1045642) of the drug efflux pump ABCB1 transporter that predicted a positive analgesic response to the combination of morphine and nortriptyline, but not to either monotherapy [29]. Also, clinical algorithms have been used to predict responses to treatment in patients with low back pain using tapentadol alone and in combination with pregabalin [30]. These types of approaches are badly needed as pain control moves towards using sensory phenotypes and other potential predictors.

Optimizing the potential benefits of combination pharmacotherapy

Providing the optimal balance between beneficial and adverse drug effects is central to optimizing outcomes with combination pharmacotherapy. Table 21.2 lists several considerations for optimal combination pharmacotherapy in chronic pain. Emphasizing the combination of analgesic agents that have the best possible efficacy and safety is perhaps the first, and most intuitive, principle of optimal combination therapy. Ensuring the best possible understanding of potential pharmacokinetic (e.g., understanding time courses of individual drug levels and actions) and pharmacodynamics interactions between the combined drugs is also critical to optimize the selection and implementation of specific drug combinations [31].

Safety issues

Avoiding and preventing adverse drug interactions is likely the first and foremost safety consideration for combination pharmacotherapy [32]. One example relevant to chronic pain comes from case reports and/or in vitro studies indicating that combining two or more serotonin reuptake inhibiting antidepressant drugs (e.g. serotonin‐specific reuptake inhibitors, serotonin‐norepinephrine reuptake inhibitors, tricyclic antidepressants, tramadol) may increase the risk of developing serotonin syndrome (a potentially life-threatening adverse drug reaction associated with changes in mental status, autonomic hyperactivity and neuromuscular dysfunction) [33, 34]. Another example of a possible safety concern is related to combining drugs that share the adverse effect of electrocardiographic QT prolongation, which has been reported with tricyclic antidepressants, SNRI antidepressants and methadone such that combining agents with these effects can increase the risk of torsades de pointes – a lethal cardiac arrhythmia [34]. Yet other potential interactions [34] come from reports of increased risk of gastrointestinal bleeding when non-steroidal anti-inflammatory drugs are co-administered with antidepressants (e.g. amitriptyline, venlafaxine).

Table 21.2 Considerations for optimal combination pharmacotherapy in chronic pain†

Characteristics of each agent in the combination:

maximal efficacy, minimal toxicity and minimal adverse interactions with other commonly used medications

minimal adverse drug interactions with other component(s) of the combination

minimal overlap of adverse effects for each component of the combination§

different pharmacological mechanism^*

different site of action^*

^† N.B. These are general considerations to be applied to a generic treatment combination. However, other unique considerations may arise for specific combinations and certain pain conditions. Adapted from: Gilron I, Jensen TS, Dickenson AH. (2013) Combination pharmacotherapy for management of chronic pain: from bench to bedside. Lancet Neurol12(11):1084‐95.

^§ Optimal combinations include treatments with differing adverse effect profiles (e.g. NSAID+SNRI antidepressant). However, many available effective treatments for some conditions such as neuropathic pain have similar side effect profiles (e.g. central nervous system depression). Despite this, some of these treatments have still been shown to provide added benefit in combination without substantial overlap of side effects.

^* Theoretically, combining treatments with different pharmacological mechanisms and/or sites of action could be expected to provide maximal synergy. However, it should be noted that some examples have been described where treatments with common mechanisms and/or sites of action can provide added benefit.

Identifying combinations with an optimal therapeutic profile

Combining two drugs with complementary analgesic mechanisms, and also with different side effect profiles, may provide an optimal therapeutic profile compared to monotherapy. For example, treatment of postoperative pain with NSAIDs (which are associated with a low incidence of sedation, nausea and vomiting) often result in less pain, sedation and nausea/vomiting when combined with opioids, partly due to analgesia-related reductions in patient-administered opioid doses [35]. However, commonly used treatments for some conditions (such as neuropathic pain), such as antidepressants, anticonvulsants and opiods, cause CNS depressant effects [5]. As such, the benefits of combining such CNS depressants may be more difficult to appreciate in this setting given the possibility that adverse effects may also be additive. However, previous studies have indicated that some combinations can provide overall benefit superior to that of monotherapy. Three trials by Gilron et. al. evaluated combinations of gabapentin plus morphine [36], nortriptyline plus gabapentin [37] and morphine plus nortriptyline [38]

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