We searched Medline between January, 1946, and March, 2013, with the following keywords: “pain*” OR “analgesi*” OR “nocicepti*” OR “antinocicepti*” OR “neuralgia” OR “fibromyalgia” OR “sciatica”; AND “combin*” OR “cotreat*” OR “co-treat*” OR “coadminist*” OR “co-administ*” OR “synerg*” OR “isobol*” OR “add on*” OR “add-on*”. From the results, we identified preclinical investigations, randomised controlled trials, other observational studies of interventions, and reviews. We also searched by
ReviewCombination pharmacotherapy for management of chronic pain: from bench to bedside
Introduction
Chronic pain is a common but often neglected aspect of neurological disease.1 In the USA alone, it affects about 30% of the population and is estimated to cost US$650 billion a year in health-care costs and lost productivity.2 Pharmacotherapy remains an important component of multimodal, multidisciplinary pain management. However, current drugs have limited efficacy and dose-limiting toxic effects.3 Although translational research efforts to develop more effective treatments have led to some novel agents, we have yet to address the clinical need fully.4 While awaiting better agents, and to address these limitations of current pharmacotherapy, combination drug regimens have been pursued by researchers and clinicians with the intention of improving outcomes.5, 6 Combination pharmacotherapy is used commonly for treatment of acute postoperative pain, and its use has a wide evidence base. Rational combination therapy has long been used in clinical areas such as asthma,7 oncology,8 and hypertension,9 but only more recently for pain management. Although more than half of patients with chronic pain receive two or more different analgesic drugs concurrently,10 relatively little evidence supports this practice, and experts have called for more research on the safety and efficacy of specific combination regimens.3, 11
Through knowledge of pain processing, many concurrent mechanisms of nociceptive transmission and modulation can be targeted.12 Thus, synergistic interactions between mechanistically distinct analgesic drugs might provide superior analgesia or fewer side-effects compared with monotherapy.13, 14 In this Review, we discuss preclinical literature, clinical data, and other information addressing the rationale, practice, and future directions of combination pharmacotherapy for pain. We do not review combination treatment for headache, which is discussed elsewhere.15
Section snippets
Pain mechanisms and clinical classification
Nociceptive processing represents an important alarm system to warn of tissue damage.12, 16, 17 Pain is signalled by specialised high-threshold receptors in the periphery, leading to a less well-defined emotional experience, driving the individual to escape from the noxious stimulus.18 Acute nociceptive pain occurs only in the presence of noxious stimuli and resolves shortly after removal of the stimulus. Chronic pain, however, seems to serve no purpose. It is a state in which increased
Pharmacological treatment
A major goal of pain management is to provide pain relief that is clinically meaningful, sustained, and associated with minimum and reversible adverse effects.11 Defining what is a clinically meaningful reduction in pain is challenging, and only a few studies have attempted to do so. Secondary analyses from a group of industry-sponsored chronic pain trials suggest that a 30% pain reduction is clinically meaningful.31 In some settings, a lower level of relief can be meaningful if there are few
Combination pharmacotherapy
Efficacy of single agents for chronic pain is limited, with less than a third of patients reporting at least moderate pain relief. So, there is a need either to develop new and more effective drugs or to identify favourable combinations of drugs that are already available. Several concurrent neural mechanisms of pain modulation have a role in clinical syndromes, providing a strong rationale for combination pharmacotherapy. While addressing the limitations of current treatments, intense
Optimising clinical outcomes of combination pharmacotherapy
Maximising clinical effectiveness of combination pharmacotherapy requires careful attention, to balance beneficial and adverse interactions between the coadministered treatments. The panel highlights key considerations for selection of an optimum combination in chronic pain. In view of the efficacy and tolerability limitations of current treatments, the most intuitive guiding principle would be to combine the drugs with the maximum safety and efficacy. Also, a fundamental understanding of
Current status of combination pharmacotherapy
The findings of recent studies into treatment patterns for various pain conditions10, 65, 66 suggest that about half of patients with chronic pain receive two or more different analgesic drugs concurrently. Commonly prescribed drug combinations include fixed-dose formulations of paracetamol combined either with opioids (eg, codeine) or tramadol, NSAIDs plus opioids, muscle relaxants plus opioids, antidepressants plus anticonvulsants, antidepressants plus opioids, and anticonvulsants plus
Clinical approaches to combination pharmacotherapy
Clinically speaking, a distinction should be made between different methods of introducing a two-drug combination—ie, whether the two drugs are administered simultaneously at the outset or whether the second agent is introduced sequentially (in an add-on fashion).86 In view of the need to improve patients' safety by minimising polypharmacy,87 a guiding principle is to first assess the response to one drug (drug A). If drug A is well tolerated and efficacious, this monotherapy could be continued
Conclusions and future directions
Combination pharmacotherapy for treatment of pain conditions, including those seen in neurological disorders, remains an important—and understudied—strategy. Future improvements in the development of combination strategies will be guided by enhanced preclinical strategies to predict optimum combinations, including methods to assess the interactions of multiple concurrent analgesic drugs and adverse effects relevant to patients' care. As emphasised in this Review and elsewhere,88 trials must
Search strategy and selection criteria
References (88)
- et al.
The economic costs of pain in the United States
J Pain
(2012) - et al.
No need for translation when the same language is spoken
Br J Anaesth
(2013) - et al.
The evidence for pharmacological treatment of neuropathic pain
Pain
(2010) - et al.
Cellular and molecular mechanisms of pain
Cell
(2009) Statistical analysis of drug combinations for synergism
Pain
(1992)- et al.
Alarm or curse? The pain of neuroinflammation
Brain Res Rev
(2008) - et al.
Translation of symptoms and signs into mechanisms in neuropathic pain
Pain
(2003) - et al.
Mechanisms of neuropathic pain
Neuron
(2006) - et al.
Interactions of sympathetic and primary afferent neurons following nerve injury and tissue trauma
Prog Brain Res
(1996) - et al.
A new definition of neuropathic pain
Pain
(2011)
Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes
Pain
Characteristics and frequency of malingering among patients with low back pain
Pain
Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain
Pain
Bad news from the brain: descending 5-HT pathways that control spinal pain processing
Trends Pharmacol Sci
Using screening tools to identify neuropathic pain
Pain
Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale
Pain
Assessment and treatment of psychosocial comorbidities in patients with neuropathic pain
Mayo Clin Proc
Guidelines on the management of fibromyalgia syndrome: a systematic review
Eur J Pain
Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients
Eur J Pain
Morphine, nortriptyline and their combination vs placebo in patients with chronic lumbar root pain
Pain
SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes
Neuron
Spinal cord mechanisms of pain
Br J Anaesth
Preclinical and early clinical investigations related to monoaminergic pain modulation
Neurotherapeutics
The cerebral signature for pain perception and its modulation
Neuron
Descending facilitation from the brainstem determines behavioural and neuronal hypersensitivity following nerve injury and efficacy of pregabalin
Pain
Studies on the spinal interaction of morphine and the NMDA antagonist MK-801 on the hyperesthesia observed in a rat model of sciatic mononeuropathy
Neurosci Lett
Synergistic antihypersensitive effects of pregabalin and tapentadol in a rat model of neuropathic pain
Eur J Pharmacol
Drug interactions in human neuropathic pain pharmacotherapy
Pain
Treatment considerations for patients with neuropathic pain and other medical comorbidities
Mayo Clin Proc
Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial
Lancet
Management of diabetic neuropathy by sodium valproate and glyceryl trinitrate spray: a prospective double-blind randomized placebo-controlled study
Diabetes Res Clin Pract
Nortriptyline and fluphenazine in the symptomatic treatment of diabetic neuropathy: a double-blind cross-over study
Pain
A randomised, double blind, placebo controlled crossover study of the cholecystokinin 2 antagonist L-365,260 as an adjunct to strong opioids in chronic human neuropathic pain
Neurosci Lett
A randomized, controlled trial of oxycodone versus placebo in patients with postherpetic neuralgia and painful diabetic neuropathy treated with pregabalin
J Pain
Pain associated with neurological disorders
EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision
Eur J Neurol
Combination pharmacotherapy for the treatment of neuropathic pain in adults
Cochrane Database Syst Rev
Combination pharmacotherapy for neuropathic pain: current evidence and future directions
Expert Rev Neurother
Impact of inhaled salmeterol/fluticasone propionate combination product versus budesonide on the health-related quality of life of patients with asthma
Am J Respir Med
Single agent versus combination chemotherapy in patients with advanced nonsmall cell lung carcinoma: a meta-analysis of response, toxicity, and survival
Cancer
Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials
BMJ
Clinical characteristics and patterns of healthcare utilization in patients with painful neuropathic disorders in UK general practice: a retrospective cohort study
BMC Neurol
Combination therapy in analgesia; seeking synergy
Curr Opin Anaesthesiol
Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?
BMC Neurol
Cited by (184)
Comparison of acetaminophen, ketamine, or ketorolac versus morphine in the treatment of acute renal colic: A network meta-analysis
2023, American Journal of Emergency MedicineTrends in gabapentinoid prescribing in UK primary care using the Clinical Practice Research Datalink: an observational study
2023, The Lancet Regional Health - EuropeAllosteric binding cooperativity in a kinetic context
2023, Drug Discovery TodaySynergism between metformin and analgesics/vitamin B<inf>12</inf> in a model of painful diabetic neuropathy
2022, Biomedicine and PharmacotherapyCitation Excerpt :Combination therapy with mechanistically different analgesic drugs could overcome these limitations, given that multiple mechanisms contribute to the generation of PDN, and simultaneously targeting several mechanisms may provide more effective pain relief. Additionally, combination therapy could enable the use of lower doses of individual analgesics, thereby reducing the incidence of dose-dependent side effects [5]. Metformin is considered to be the drug-of-choice for the initial treatment of type 2 diabetes, because of its high antihyperglycemic efficacy, favorable safety profile and certain cardioprotective properties [6].