Combination pharmacotherapy for management of chronic pain: from bench to bedside
ABSTRACT 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.
Article: Cancer pain physiology[Show abstract] [Hide abstract]
ABSTRACT: Mechanisms of inflammatory and neuropathic pains have been elucidated and translated to patient care by the use of animal models of these pain states. Cancer pain has lagged behind since early animal models of cancer-induced bone pain were based on the systemic injection of carcinoma cells. This precluded systematic investigation of specific neuronal and pharmacological alterations that occur in cancer-induced bone pain. In 1999, Schwei et al. described a murine model of cancer-induced bone pain that paralleled the clinical condition in terms of pain development and bone destruction, confined to the mouse femur. This model prompted related approaches, and we can now state that cancer pain may include elements of inflammatory and neuropathic pains but also unique changes in sensory processing. Cancer-induced bone pain results in progressive bone destruction, elevated osteoclast activity and distinctive nocifensive behaviours (indicating the triad of ongoing, spontaneous and movement-induced hyperalgesia). In addition, cancer cells induce an inflammatory infiltrate and release growth factors, cytokines, interleukins, chemokines, prostanoids and endothelins, resulting in a reduction of pH to below 5 and direct deformation of primary afferents within bone. These peripheral changes, in turn, drive hypersensitivity of spinal cord sensory neurons, many of which project to the parts of the brain involved in the emotional response to pain. Within the spinal cord, a unique neuronal function reorganization within segments of the dorsal horn of the spinal cord receiving nociceptive input from the bone are discussed. Changes in certain neurotransmitters implicated in brain modulation of spinal function are also altered with implications for the affective components of cancer pain. Treatments are described in terms of mechanistic insights and in the case of opioids, which modulate pain transmission at spinal and supraspinal sites, their use can be compromised by opioid-induced hyperalgesia. We discuss evidence for how this comes about and how it may be treated.09/2014; 8(4):154–162. DOI:10.1177/2049463714545136
[Show abstract] [Hide abstract]
ABSTRACT: Neuropathic pain is caused by disease or injury of the nervous system and includes various chronic conditions that, together, affect up to 8% of the population. A substantial body of neuropathic pain research points to several important contributory mechanisms including aberrant ectopic activity in nociceptive nerves, peripheral and central sensitization, impaired inhibitory modulation, and pathological activation of microglia. Clinical evaluation of neuropathic pain requires a thorough history and physical examination to identify characteristic signs and symptoms. In many cases, other laboratory investigations and clinical neurophysiological testing may help identify the underlying etiology and guide treatment selection. Available treatments essentially provide only symptomatic relief and may include nonpharmacological, pharmacological, and interventional therapies. Most extensive evidence is available for pharmacological treatment, and currently recommended first-line treatments include antidepressants (tricyclic agents and serotonin-norepinephrine reuptake inhibitors) and anticonvulsants (gabapentin and pregabalin). Individualized multidisciplinary patient care is facilitated by careful consideration of pain-related disability (eg, depression and occupational dysfunction) as well as patient education; repeat follow-up and strategic referral to appropriate medical/surgical subspecialties; and physical and psychological therapies. In the near future, continued preclinical and clinical research and development are expected to lead to further advancements in the diagnosis and treatment of neuropathic pain. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.Mayo Clinic Proceedings 04/2015; 90(4):532-545. DOI:10.1016/j.mayocp.2015.01.018 · 5.81 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Monotherapy with first-line drugs for neuropathic pain often fails to provide sufficient pain relief or has unacceptable side effects (SE) because of the need for high doses. The aim of this trial was to test whether the combination of imipramine and pregabalin in moderate doses would relieve pain more effectively than monotherapy with either of the drugs.This was a randomized, double-blind, placebo-controlled, cross-over, multicenter trial consisting of four 5 week treatment periods in patients with painful polyneuropathy. Treatment arms were imipramine 75 mg/day versus pregabalin 300 mg/day versus combination therapy versus placebo. Patients with polyneuropathy and symptoms for more than 6 months, age 20-85 years, pain intensity ≥4 on a 0-10-point numeric rating scale (NRS) and pain at least 4 days a week were included in the trial.Two-hundred-sixty-two patients were screened for participation, 73 patients were randomized and 69 patients were included in the data analysis. The effect on average pain in comparison with placebo was: combination (- 1.67 NRS points, p<0.001), imipramine (- 1.08 NRS points, p<0.001) and pregabalin (- 0,48 NRS points, p=0.03). The combination therapy had significantly lower pain scores than both monotherapies: combination vs imipramine (p=0.009), combination vs pregabalin (p<0.001). During combination therapy, the dropout rate was higher and the patients reported a higher rate and severity of SE.Combination of moderate doses of TCA and pregabalin could be considered as an alternative to high- dosage monotherapy. However, the trial also emphasized that balance between efficacy and safety is an issue.Pain 02/2015; DOI:10.1097/j.pain.0000000000000143 · 5.84 Impact Factor