Safety concerns with long-term opioid use

Harned, Michael E.; Sloan, Paul A.

doi:10.1080/14740338.2016.1177509

Cited by 46 publications

(23 citation statements)

References 70 publications

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“…While opioids are strong analgesics, their use is hampered by engagement of opponent processes resulting in tolerance, hyperalgesia, and negative affect [28]. We and others have shown The gut microbiota mediates reward and sensory responses associated with.…”

Section: Discussionmentioning

confidence: 90%

The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence

Lee

Vuong²,

Nusbaum³

et al. 2018

Neuropsychopharmacol

143

121

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Opioid use for long-term pain management is limited by adverse side effects, such as hyperalgesia and negative affect. Neuroinflammation in the brain and spinal cord is a contributing factor to the development of symptoms associated with chronic opioid use. Recent studies have described a link between neuroinflammation and behavior that is mediated by a gut-brain signaling axis, where alterations in indigenous gut bacteria contribute to several inflammation-related psychopathologies. As opioid receptors are highly expressed within the digestive tract and opioids influence gut motility, we hypothesized that systemic opioid treatment will impact the composition of the gut microbiota. Here, we explored how opioid treatments, and cessation, impacts the mouse gut microbiome and whether opioid-induced changes in the gut microbiota influences inflammation-driven hyperalgesia and impaired reward behavior. Male C57Bl6/J mice were treated with either intermittent or sustained morphine. Using 16S rDNA sequencing, we describe changes in gut microbiota composition following different morphine regimens. Manipulation of the gut microbiome was used to assess the causal relationship between the gut microbiome and opioid-dependent behaviors. Intermittent, but not sustained, morphine treatment was associated with microglial activation, hyperalgesia, and impaired reward response. Depletion of the gut microbiota via antibiotic treatment surprisingly recapitulated neuroinflammation and sequelae, including reduced opioid analgesic potency and impaired cocaine reward following intermittent morphine treatment. Colonization of antibiotic-treated mice with a control microbiota restored microglial activation state and behaviors. Our findings suggest that differing opioid regimens uniquely influence the gut microbiome that is causally related to behaviors associated with opioid dependence.

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Section: Discussionmentioning

confidence: 90%

The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence

Lee

Vuong²,

Nusbaum³

et al. 2018

Neuropsychopharmacol

143

121

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“…Of these, constipation is a major compliant among patients (Harned and Sloan, 2016). Here we demonstrated that a CB2 agonist alone does not slow GI transit and reports in humans did not observe GI disturbances or bleeding (clinical trial.gov), yet morphine alone resulted in a significant inhibition of GI transit.…”

Section: Discussionmentioning

confidence: 99%

Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists

et al. 2017

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The misuse of prescription opiates is on the rise with combination therapies (e.g. acetaminophen or NSAIDs) resulting in severe liver and kidney damage. In recent years, cannabinoid receptors have been identified as potential modulators of pain and rewarding behaviors associated with cocaine, nicotine and ethanol in preclinical models. Yet, few studies have identified whether mu opioid agonists and CB2 agonists act synergistically to inhibit chronic pain while reducing unwanted side effects including reward liability. We determined if analgesic synergy exists between the mu-opioid agonist morphine and the selective CB2 agonist, JWH015, in rodent models of acute and chronic inflammatory, post-operative, and neuropathic pain using isobolographic analysis. We also investigated if the MOR-CB2 agonist combination decreased morphine-induced conditioned place preference (CPP) and slowing of gastrointestinal transit. Co-administration of morphine with JWH015 synergistically inhibited preclinical inflammatory, post-operative and neuropathic-pain in a dose- and time-dependent manner; no synergy was observed for nociceptive pain. Opioid-induced side effects of impaired gastrointestinal transit and CPP were significantly reduced in the presence of JWH015. Here we show that MOR + CB2 agonism results in a significant synergistic inhibition of preclinical pain while significantly reducing opioid-induced unwanted side effects. The opioid sparing effect of CB2 receptor agonism strongly supports the advancement of a MOR-CB2 agonist combinatorial pain therapy for clinical trials.

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“…Labianca et al., ). However, the influence of morphine and other opioids on sleep‐disordered breathing, including central sleep apnoea, has recently been investigated more carefully (Zutler and Holty, ; Jungquist et al., ; Javaheri et al., ; Rose et al., ; Harned and Sloan, ). A recent systematic review found the overall prevalence of central sleep apnoea among patients taking chronic opioids to be 24% (Correa et al., ).…”

Section: Assessmentmentioning

confidence: 99%

“…The risk appeared to be linearly related to escalating opioid doses, with the morphine equivalent daily dose and risk of sleep disordered breathing being strongly associated. The authors concluded that an morphine equivalent daily dose of 200 mg or greater was a risk factor for severity of central sleep apnoea (Correa et al., ; Harned and Sloan, ).…”

Section: Assessmentmentioning

confidence: 99%

Update of the Scientific Opinion on opium alkaloids in poppy seeds

Knutsen¹,

Alexander²,

Barregård³

et al. 2018

EFS2

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Poppy seeds are obtained from the opium poppy (Papaver somniferum L.). They are used as food and to produce edible oil. The opium poppy plant contains narcotic alkaloids such as morphine and codeine. Poppy seeds do not contain the opium alkaloids, but can become contaminated with alkaloids as a result of pest damage and during harvesting. The European Commission asked EFSA to provide an update of the Scientific Opinion on opium alkaloids in poppy seeds. The assessment is based on data on morphine, codeine, thebaine, oripavine, noscapine and papaverine in poppy seed samples. The CONTAM Panel confirms the acute reference dose (ARfD) of 10 lg morphine/kg body weight (bw) and concluded that the concentration of codeine in the poppy seed samples should be taken into account by converting codeine to morphine equivalents, using a factor of 0.2. The ARfD is therefore a group ARfD for morphine and codeine, expressed in morphine equivalents. Mean and high levels of dietary exposure to morphine equivalents from poppy seeds considered to have high levels of opium alkaloids (i.e. poppy seeds from varieties primarily grown for pharmaceutical use) exceed the ARfD in most age groups. For poppy seeds considered to have relatively low concentrations of opium alkaloids (i.e. primarily varieties for food use), some exceedance of the ARfD is also seen at high levels of dietary exposure in most surveys. For noscapine and papaverine, the available data do not allow making a hazard characterisation. However, comparison of the dietary exposure to the recommended therapeutical doses does not suggest a health concern for these alkaloids. For thebaine and oripavine, no risk characterisation was done due to insufficient data. However, for thebaine, limited evidence indicates a higher acute lethality than for morphine and the estimated exposure could present a health risk.

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Safety concerns with long-term opioid use

Cited by 46 publications

References 70 publications

The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence

The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence

Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists

Update of the Scientific Opinion on opium alkaloids in poppy seeds

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