Combination drug therapy for chronic pain: a call for more clinical studies

Abstract

Chronic pain is a debilitating clinical condition associated with a variety of disease entities including diabetic neuropathy, postherpetic neuralgia, low back pathology, fibromyalgia, and neurological disorders. For many general practitioners and specialists, managing chronic pain has become a daunting challenge. As a modality of multidisciplinary chronic pain management, medications are often prescribed in combinations, an approach referred to as combination drug therapy (CDT). However, many medications for pain therapy, including antidepressants and opioid analgesics, have significant side effects that can compound when used in combination and impact the effectiveness of CDT. To date, clinical practice of CDT for chronic pain has been based largely on clinical experiences. In this article, we will focus on (1) the scientific basis and rationales for CDT, (2) current clinical data on CDT, and (3) the need for more clinical studies to establish a framework for the use of CDT.

Perspective: More preclinical, clinical, and translational studies are needed to improve the efficacy of combination drug therapy that is an integral part of a comprehensive approach to the management of chronic pain.

Figure 1. Multiple mechanisms underlying chronic pain serve as targets for pharmacotherapy including CDT

A. While specific mechanisms may vary in association with an array of biological and social factors, several fundamental processes may serve as particularly good targets for available drugs. These processes include (1) transduction, which involves the conversion of thermal, mechanical and/or chemical stimuli in the local environment into a neural signal (action potential), (2) transmission of the neural signal in both peripheral and central axons, which is essential for the propagation of nociceptive signal from sites of injury or disease to cortical structures necessary for the perception of pain, (3) neuroplastic changes such as ectopic activity at the DRG (3a), synaptic transmission (3b), and descending modulation (3c) such as endogenous inhibitory processes that involves neural processes arising from brainstem nuclei that impact nociceptive input at the level of the spinal cord and trigeminal dorsal horn and can be facilitated with a number of drugs currently available. The final steps underlying the perception of pain (4) involve a number of cortical structures important for the sensory, emotional and cognitive aspects of pain. B. Currently available drugs can be used to attenuate pain via actions at all potential targets where the efficacy of specific classes of drug is likely to be determined by the relative involvement of a particular target in a particular pain phenotype. NSAID: non-steroidal anti-inflammatory drug; TCA: tricyclic antidepressant; SNRI: selective serotonin and norepinephrine re-uptake inhibitor; COX-2: cyclooxygenase-2; TNFα: tumor necrosis factorα.

Figure 2. A list of possible side effects with CDT

Examples of adverse effects from various drug combinations are shown in individual boxes. Common side effects such as nausea and dizziness could be exacerbated in any drug combination.