The dark side of opioids in pain management: basic science explains clinical observation

Abstract

Introduction: In the past 2 decades, opioids have been used increasingly for the treatment of persistent pain, and doses have tended to creep up. As basic science elucidates mechanisms of pain and analgesia, the cross talk between central pain and opioid actions becomes clearer.

Objectives: We aimed to examine the published literature on basic science explaining pronociceptive opioid actions, and apply this knowledge to clinical observation.

Methods: We reviewed the existing literature on the pronociceptive actions of opioids, both preclinical and clinical studies.

Results: Basic science provides a rationale for the clinical observation that opioids sometimes increase rather than decrease pain. Central sensitization (hyperalgesia) underlies pain chronification, but can also be produced by high dose and high potency opioids. Many of the same mechanisms account for both central pain and opioid hyperalgesia.

Conclusion: Newly revealed basic mechanisms suggest possible avenues for drug development and new drug therapies that could alter pain sensitization through endogenous and exogenous opioid mechanisms. Recent changes in practice such as the introduction of titration-to-effect for opioids have resulted in higher doses used in the clinic setting than ever seen previously. New basic science knowledge hints that these newer dosing practices may need to be reexamined. When pain worsens in a patient taking opioids, can we be assured that this is not because of the opioids, and can we alter this negative effect of opioids through different dosing strategies or new drug intervention?

Keywords: Central sensitization; Hyperalgesia; Opioids; Pain chronification.

Figure 1.

General view of opioid-induced pain sensitization. Peripheral changes may occur in the primary afferent neurons through enhanced expression in transient receptor potential vanilloid 1 and activity of the protein kinase-A (PKA) and up-regulation of IL-1β in satellite cells that produce increased release, in the dorsal horn of the spinal cord, of excitatory peptides such substance P (SP) and calcitonin gene-related peptide (CGRP) and of glutamate. In addition, at the spinal cord, a complex interplay between neurons and glial cells may occur. Neurons are sensitized by mammalian target of rapamycin (mTOR)-dependent mechanisms after opioid administration. Activated glial cells through direct (TLR4) and/or indirect action of opioid may produce the release of chemokines, cytokines, and Brain-derived neurotrophic factor (BDNF) that sensitize neurons leading to overactivity of ascending pain pathways. Activation of descending facilitatory pain pathways after opioid administration through the increase in cholecystokinin (CCK) into the rostral ventromedial medulla (RVM), facilitate the release of excitatory peptide in the spinal cord contributing to the maintenance of long-lasting pain sensitization after short-term opioid exposure.

Figure 2.

Hypothesis on the transition from acute to chronic facilitate by opioid administration. Acute tissue or nerve injury produces an increased activity in pain facilitatory systems that can be exaggerated by treatment with high doses of opioid. After remission and cessation of opioid administration, increased endogenous pain inhibition through opioid and α2A adrenergic receptors constitutive activity suppress sustained hyperalgesia that may depend on epigenetic alterations at BDNF and proDyn gene expression, protein kinase-A in primary afferent neurons and increased expression of the pro-inflammatory cytokines IL-1β. This results in the development of latent pain sensitization that may be associated with long-term pain vulnerability that could facilitate the development of chronic pain.