Chronic Opioid Use in Fibromyalgia Syndrome

A Clinical Review

Jacob T. Painter, PharmD, MBA, PhD; Leslie J. Crofford, MD

Disclosures

J Clin Rheumatol. 2013;19(2):72-77. 

In This Article

Biologic Effects of Opioids

The biologic effects of opioids are mediated by receptors expressed in the brain, spinal cord, and in the periphery.[6] These receptors are associated with a range of psychological and physiologic effects from binding of endogenous and/or exogenous ligands. In the brain, the opioid system mediates hedonic evaluation, or pleasure, associated with natural rewards.[6] There is a complex relationship between endogenous opioid peptides and the mesolimbic dopamine that is the principal mediator of reward and reinforcement. In general, proenkephalin enhances dopaminergic activity via μ-opioid receptors, whereas prodynorphin inhibits dopaminergic activity via [kappa]-opioid receptors.[6] It is likely that chronic opioid administration in patients with musculoskeletal pain is associated with neuroplastic changes in the brain. These central adaptations may produce the clinical picture of dependence, opioid-seeking behaviors, and difficulty in weaning patients off opioid medications.

It has long been known that some patients receiving opioid medication over time may need to increase the dose to maintain analgesia.[7] Physicians typically attribute the development of inadequate analgesia over time to the pharmacologic phenomenon of tolerance related to adaptive cellular changes associated with reduced turnover rate and number of opioid receptors or desensitization of opioid receptors to ligand, or both.[8,9] Another phenomenon, opioid-induced hyperalgesia, may be difficult to distinguish from pharmacologic tolerance clinically. However, opioid-induced hyperalgesia is thought to be due predominantly to central sensitization of pronociceptive pathways and is associated with reduced nociceptive threshold.[7,8] In contrasting opioid-induced hyperalgesia with tolerance, patients who are tolerant have no increase in baseline pain sensitivity but require increased doses of opioids over time to achieve a level of analgesia previously reached with a lower dose, whereas patients with opioid-induced hyperalgesia exhibit a lower pain threshold and an increase in pain perception.

Opioid analgesics provide their analgesic effects by acting on opioid receptors μ, δ, and κ.[10] Endogenous opioid peptides include enkephalin, β-endorphin, prodynorphin, and nociceptin/orphanin FQ, which acts on the opioid receptor–like 1 receptor.[10] These are G-protein–linked receptors with complex intracellular signaling pathways. Exogenous opioid receptor agonists produce analgesic effects when injected into sites such as the periaqueductal gray, rostral ventromedial medulla, amygdala, insula, or spinal cord by acting on these classic opioid receptors.[6] The rostral ventral medulla is a key region for balancing descending modulation of pain. At spinal sites, ligands for the classic opioid receptors can produce an analgesic effect by reducing excitatory amino acid and neuropeptide release from primary afferents and by direct postsynaptic inhibition of central neurons that are activated by noxious stimulation.

Recent evidence indicates that, in addition to the actions of opioids on neurons and other cells via classic opioid receptors, opioids may act on spinal glia via opioid receptor–independent pathways.[11] It has become increasingly recognized that sensitization of pain transmission pathways involves activation of microglia and astrocytes, which leads to a proinflammatory phenotype that can be induced by opioids.[12] The mechanism underlying this phenomenon appears to involve opioid-induced signaling through Toll-like receptor 4, an effect proposed to oppose opioid analgesia and increase pronociception or central pain amplification.[13]

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