Mechanisms of pain transmission and pharmacologic management

Pain sensation involves multiple signaling and modulatory pathways, employing a variety of neurotransmitters and other mediators. Inhibitory and facilitatory mechanisms affect the perception of stimuli as painful or non-painful, and in addition may affect the perceived intensity of pain. Endogenous opioids are key mediators in the descending pain suppression pathways. Additionally, monoaminergic neurotransmitters such as norepinephrine, serotonin and dopamine positively or negatively modulate pain signaling, depending on receptor type and location. The various mediators involved in pain signaling provide potential targets for pharmacological interventions. Single analgesic therapies may be limited in their ability to comprehensively target these complex pain signaling pathways. Therapeutic approaches acting on multiple pain transmission pathways through different mechanisms of action provide an opportunity to maximize efficacy and tolerability in the treatment of pain.

This article discusses the various physiologic processes involved in pain signaling and modulation, describes the mechanisms by which various classes of analgesic agents are believed to produce their clinical effects, and explores the potential benefits of a multiple-mechanism approach to analgesia. Published articles describing the physiologic processes involved in pain signaling and modulation and the mechanisms of analgesia for different drug classes were reviewed. MEDLINE searches were conducted to identify relevant studies published through August 2009 that evaluated the efficacy and tolerability of multiple-mechanism analgesic regimens. English language-only randomized controlled trials and meta-analyses of randomized controlled trials were considered.

Multiple neurotransmitters and other mediators are involved in the endogenous modulation of pain signaling, providing numerous opportunities for intervention with different classes of analgesics. Data from numerous clinical trials indicate that multiple-mechanism approaches to analgesia provide comparable or superior analgesic efficacy with lower doses of the individual agents and reduced incidence of side effects. These data support current guidelines which endorse multiple-mechanism strategies for both acute and chronic pain management.