Opioids Prolonging Hyperalgesia?

Involvement of microglia, inflammation

Though the long-term use of opioids for chronic pain treatment has increased significantly, there is a lack of evidence supporting this approach.1 As a result, experts are concerned that it may be ineffective or even harmful because of the paradoxical opioid-induced hyperalgesia (OIH) that has been observed.2 

New research reported in the Proceedings of the National Academy of Sciences aimed to investigate this effect in a rodent model of chronic pain.3 Numerous instances of OIH in chronic pain populations have been reported, in which pain is exacerbated by chronic opioid use.4-6 

The underlying mechanisms are not well understood, due to a lack of preclinical studies and because OIH duration has never been evaluated after treatment was discontinued. 

The authors of the present study cited 3 lines of evidence to support their prediction that opioid administration would increase long-term neuropathic pain: 

  • Following peripheral nerve injury, spinal release of danger-associated molecular patterns (DAMPs) activates the Toll-like receptor 4 (TLR4) signaling pathway, resulting in spinal microglial reactivity.
  • Opioids also activate TLR4, leading to release of pro-inflammatory mediators (including Interleukin 1β [Il-1β] and Nuclear Factor NF-κB).7
  • Previous research has described a “two-hit hypothesis of microglial priming” in which the neuroinflammatory response is enhanced upon secondary challenge.8 In this model, peripheral nerve injury-related neuropathic pain is considered ‘hit 1;’ this pain can be exacerbated by opioid treatment (hit 2). 

 Authors therefore hypothesized that the concurrent opioid treatment and peripheral nerve injury might trigger a novel mechanism, distinct from known pathways activated in the spinal cord, or in response to opioids or pain. In such a mechanism, inflammasome-activated Il-1β would act as a “gatekeeper of inflammation.” 

In the current study, a rodent model was used to investigate whether administration of morphine following peripheral nerve injury would result in persistent neuropathic pain. Starting 10 days following sciatic chronic constriction injury (CCI) or sham surgery, animals were administered morphine (5mg/kg) or saline twice daily for 5 days. 

Results show that the brief course of morphine prolonged the duration of CCI-induced allodynia following treatment cessation (P <.001). This is the first study to report such an effect. The researchers also confirmed that this effect was mediated by dorsal spinal microglial reactivity, as well as NOD-like receptor protein 3 (NLRP3) inflammasome and related activation of IL-1β. 

They further discovered that they could both prevent and reverse the morphine-induced allodynia by treating animals with clozapine-N-oxide, a ligand of the novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). This result indicates that persistent OIH can be disrupted and that pain levels can be reset to normal. 

Further research is needed to confirm these effects in the clinical setting, and the present findings provide a rationale for investigations into whether treatment of chronic pain with opioids paradoxically contributes to pain maintenance.  

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  1. Manchikanti L, Fellows B, Ailinani H, Pampati V. Therapeutic use, abuse, and nonmedical use of opioids: A ten-year perspective. Pain Physician. 2010; 13(5):401–435. 
  2. Grace PM, Maier SF, Watkins LR. Opioid-induced central immune signaling: implications for opioid analgesia. Headache. 2015; 55(4):475–489.
  3. Grace PM, Strand KA, Galer EL, et al. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci USA. 2016; 113(24):E3441-3450.
  4. Hooten WM, Lamer TJ, Twyner C. Opioid-induced hyperalgesia in community-dwelling adults with chronic pain. Pain. 2015; 156(6):1145–1152. 
  5. Suzan E, Eisenberg E, Treister R, Haddad M, Pud D. A negative correlation between hyperalgesia and analgesia in patients with chronic radicular pain: Is hydromorphone therapy a double-edged sword? Pain Physician. 2013; 16(1):65–76.
  6. Ram KC, Eisenberg E, Haddad M, Pud D. Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain – new perspective of opioid-induced hyperalgesia. Pain. 2008; 139(2):431–438. 
  7. Wang X, Loram LC, Ramos K, et al. Morphine activates neuroinflammation in a manner parallel to endotoxin. Proc Natl Acad Sci USA. 2012;109(16):6325-6330.
  8. Frank MG, Baratta MV, Sprunger DB, Watkins LR, Maier SF. Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav Immun. 2007;  21(1):47–59.