Combination pharmacotherapy for management of chronic pain: From bench to bedside

Departments of Anaesthesiology and Perioperative Medicine and Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada. Electronic address: .
The Lancet Neurology (Impact Factor: 21.9). 09/2013; 12(11). DOI: 10.1016/S1474-4422(13)70193-5
Source: PubMed


Chronic pain, a frequently neglected problem, is treated with different classes of drugs. Current agents are limited by incomplete efficacy and dose-limiting side-effects. Knowledge of pain processing implicates multiple concurrent mechanisms of nociceptive transmission and modulation. Thus, synergistic interactions of drug combinations might provide superior analgesia and fewer side-effects than monotherapy by targeting of multiple mechanisms. Several trials in neuropathic pain, fibromyalgia, arthritis, and other disorders have assessed various two-drug combinations containing antidepressants, anticonvulsants, non-steroidal anti-inflammatories, opioids, and other agents. In some trials, combined treatment showed superiority over monotherapy, but in others improved benefit or tolerability was not seen. Escalating efforts to develop novel analgesics that surpass the efficacy of current treatments have not yet been successful; therefore, combination therapy remains an important beneficial strategy. Methodological improvements in future translational research efforts are needed to maximise the potential of combination pharmacotherapy for pain.

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    • "A promising strategy is combination therapy, which requires combining two or more drugs as a pharmacotherapy and has been successfully practiced for treating various diseases including pain (Orrù et al. 2014; Smith 2008). The overall aim of combination therapy is to increase the analgesic effectiveness of analgesics such as opioids and/or reduce unwanted effects as smaller doses of individual drugs may be needed (Smith 2008; Gilron et al. 2013). "
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    ABSTRACT: Emerging preclinical evidence suggests that imidazoline I2 receptor ligands may be effective analgesics. Quantitative analysis of the combined I2 receptor ligands and opioids is needed for the justification of combination therapy. This study systematically examined the anti-hyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with oxycodone in rats. Von Frey filament test was used to examine the anti-hyperalgesic effects of drugs in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. Schedule-controlled responding was used to assess the rate-altering effects of study drugs. Duration of actions of individual drugs (2-BFI, phenyzoline, and oxycodone) alone or in combination was studied. Dose-addition analysis was employed to assess the anti-hyperalgesic interactions between drugs. Oxycodone (0.1-3.2 mg/kg, i.p.), 2-BFI (1-17.8 mg/kg, i.p.), and phenyzoline (17.8-56 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and oxycodone produced additive interactions while phenyzoline and oxycodone produced supra-additive interactions under all fixed ratios. The same drug combinations did not alter or significantly reduced the operant responding depending on the ratios of the drug combinations. Quantitative analysis of the anti-hyperalgesic effects of I2 receptor ligands strongly supports the therapeutic potential of I2 receptor ligands against inflammatory pain. In addition, the data reveal that phenyzoline is superior to the prototypic I2 receptor ligand 2-BFI for the management of pain and warrants further consideration as a novel analgesic.
    Psychopharmacology 06/2015; 232(18). DOI:10.1007/s00213-015-3983-1 · 3.88 Impact Factor
    • "And finally, the use of combination therapy when treating neuropathic pain may be a useful strategy, as the use of multiple pharmacological agents can target multiple mechanisms, and often results in reduced dosing , and thus a reduction in side effect profile without loss of efficacy. Although this is intellectually appealing enhanced efficacy of combined versus monotherapy for neuropathic pain has not yet been firmly established (Gilron et al., 2013; Finnerup et al., 2015). "
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    ABSTRACT: Maladaptive plasticity within the dorsal horn of the spinal cord is a key substrate for development of neuropathic pain following peripheral nerve injury. Advances in genetic engineering, tracing techniques and opto-genetics are leading to a much better understanding of the complex circuitry of the spinal dorsal horn and the radical changes evoked in such circuitry by nerve injury. These changes can be viewed at multiple levels including: synaptic remodelling including enhanced excitatory and reduced inhibitory drive, morphological and electrophysiological changes which are observed both to primary afferent inputs as well as dorsal horn neurons, and ultimately circuit-level rewiring which leads to altered connectivity and aberrant processing of sensory inputs in the dorsal horn. The dorsal horn should not be seen in isolation but is subject to important descending modulation from the brainstem, which is further dysregulated by nerve injury. Understanding which changes relate to specific disease-states is essential, and recent work has aimed to stratify patient populations in a mechanistic fashion. In this review we will discuss how such pathophysiological mechanisms may lead to the distressing sensory phenomena experienced by patients suffering neuropathic pain, and the relationship of such mechanisms to current and potential future treatment modalities. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 05/2015; 300. DOI:10.1016/j.neuroscience.2015.05.020 · 3.36 Impact Factor
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    • "Pain is a complex pathophysiology that, in many instances, is associated with a number of comorbidities such as cognitive impairment and depression (Moriarty, 2011; Li, 2015). Although combination therapies for pain and other indications are used often (Gilron et al., 2013; Rodon et al., 2010), combined treatment with multiple drugs presents several difficulties that might be overcome through therapeutic miRNAs or through a combination of miRNA approaches and small molecules, though considerable work remains (Li and Rana, 2014). This approach has been highlighted recently by Lötsch and colleagues in an interesting article on the use of functional genomics and computational analyses of molecular interaction networks involved in the genetics of pain (Lötsch et al., 2013). "
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    ABSTRACT: Berend Olivier has had a long-standing interest in the utility of animal models for a wide variety of therapeutic indications. His work has spanned multiple types of models, blending ethological, or species typical and naturalistic behaviors, along with methodologies based on learned behavior. He has consistently done so, from an analytical as well as predictive perspective, and has made multiple contributions while working in both the pharmaceutical industry and within an academic institution. Although focused primarily on psychiatric disorders, Berend has conducted research in the area of pain in humans and in animals, demonstrating an expansive appreciation for the breadth, scope and significance of the science and applications of the discipline of pharmacology to these diverse areas. This review focuses on the use of animal models in pain research from the perspective of the long-standing deficiencies in the development of therapeutics in this area and from a preclinical perspective where the translational weaknesses have been quite problematic. The challenges confronting animal models of pain, however, are not unique to this area of research, as they cut across several therapeutic areas. Despite the deficiencies, failures and concerns, existing animal models of pain continue to be of widespread use and are essential to progress in pain research as well as in other areas. Although not focusing on specific animal models of pain, this article seeks to examine general issues facing the use of these models. It does so by exploring alternative approaches which capture recent developments, which build upon principles and concepts we have learned from Berend's contributions, and which provide the prospect of helping to address the absence of novel therapeutics in this area. Copyright © 2015. Published by Elsevier B.V.
    European Journal of Pharmacology 01/2015; 753. DOI:10.1016/j.ejphar.2014.11.046 · 2.53 Impact Factor
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