Elsevier

Drug and Alcohol Dependence

Volume 200, 1 July 2019, Pages 6-13
Drug and Alcohol Dependence

Full length article
Sensitized brain response to acute pain in patients using prescription opiates for chronic pain: A pilot study

https://doi.org/10.1016/j.drugalcdep.2019.02.024Get rights and content

Highlights

  • Individuals usindg prescription opiates have elevated brain responses to pain.

  • Larger doses of prescription opiates are associated with larger brain responses.

  • Higher current pain was associated with reduced responses to experimental pain.

Abstract

Background

Chronic opiate use leads to a sensitized behavioral response to acute pain, which in turn, leads to escalating doses of opiates. This study was designed to test the hypothesis that chronic opiate usage is also associated with a sensitized neurobiological response to acute pain in individuals that have used prescription opiates for 6 or more months.

Methods

Fourteen patients with non-alcoholic chronic pancreatitis that have been taking prescription opiates for 6 or more months and 14 gender matched, non-opiate using controls were enrolled. Functional neuroimaging data was acquired while participants received blocks of thermal stimulation to their wrist (individually-tailored to their pain threshold).

Results

Self-reported pain was significantly greater in opiate using patients (3.4 ± 3.4) than controls (0.2 ± 0.8: Brief Pain Inventory p < 0.005), however no significant difference between groups was observed in the individually-tailored pain thresholds. Opiate using patients evidenced a significantly greater response to pain than controls in two established nodes of the “Pain Matrix”: somatosensory cortex (pFWE≤0.001) and anterior cingulate cortex (p ≤ 0.01). This response was positively correlated with prescribed morphine equivalent dosages (average: 133.5 ± 94.8 mg/day).

Conclusion

The findings suggest that in chronic pancreatitis patients, a dose of opiates that normalizes their behavioral response to acute pain is associated with an amplified neural response to acute pain. Further longitudinal studies are needed to determine if this neural sensitization hastens a behavioral tolerance to opiates or the development of an opioid use disorder.

Introduction

In 2014, there were 245 million prescriptions for opiates written in the United States (Volkow and McLellan, 2016). Unfortunately, the widespread availability of these powerful analgesic drugs has led to a public health crisis and increases in mortality and morbidity associated with chronic prescribing. In 2015, 33,000 individuals had fatal overdoses caused by licit and illicit opioids (Rudd et al., 2016). Despite recent success in reducing the overall number of prescriptions, prescribing rates have remained high (Guy et al., 2017). The increased availability of opiates places many individuals at risk of conversion to opiate use disorder (Volkow et al., 2018), and with chronic use individuals are susceptible to a paradoxical increased sensitivity to pain known as opioid-induced hyperalgesia (Lee et al., 2011; Nusrat et al., 2012).

Decades of preclinical work has elucidated several mechanisms by which opiate usage can lead to states of hyperalgesia (Angst and Clark, 2006; Ossipov et al., 2005; Roeckel et al., 2016; Simonnet and Rivat, 2003). One commonly uncovered mechanism operating at the peripheral and spinal levels is NMDA-dependent, long-term potentiation (LTP) (Drdla et al., 2009; Zhou et al., 2010) at nociceptive afferents. These findings have been translated to clinical practice, with meta-analyses supporting the effectiveness of ketamine, an NMDA antagonist, in reducing post-surgical pain (Wu et al., 2015). Preclinical work has also uncovered alterations at the supraspinal level, with evidence for facilitory, pronociceptive activity within the rostral ventromedial medulla and periaqueductal gray (Rivat et al., 2009; Vanderah et al., 2001), as well as increases in protein kinase activity across the cortex (Sanna et al., 2014). In humans, the supraspinal mechanisms through which chronic prescription opiate usage alters brain reactivity to pain are not well understood, though neuroimaging is uncovering the regions involve in pain processing. Functional magnetic resonance imaging (fMRI) studies of acute pain in healthy individuals demonstrate that there is a reliable network of brain regions (the “Pain Matrix”) which are engaged by an acutely painful stimulus (Apkarian et al., 2005; Cauda et al., 2014; Tanasescu et al., 2016; Wager et al., 2013). These brain regions include: (1) the anterior cingulate cortex (ACC) and insula, which are primary nodes in the “Salience Network” (Seeley et al., 2007); (2) the somatosensory cortex and thalamus, which are primary sensory processing areas and their subcortical afferent; (3) as well as prefrontal regions and brainstem nuclei (Melzack, 2001; Petrovic et al., 2004). Positron emission tomography (PET) studies demonstrate that several of these areas have high endogenous opiate receptor levels, including the ACC (Vogt et al., 1995), insula (Baumgartner et al., 2006), and thalamus. Additionally, acute experimental pain evoked with the application of a thermal stimulus leads to an increase in opiate receptor binding specifically in the ACC and insula among healthy individuals (Sprenger et al., 2006). A recent meta-analysis demonstrated that the brain response to acute pain in chronic pain patients is similar to healthy controls (Tanasescu et al., 2016). Notably, however, none of these studies examined how opiate usage affects the pain response, with many studies excluding patients who use opiates. Given that the brain regions involved in processing acute pain contain high levels of opiate receptors, it is possible that chronic opiate use in individuals with chronic pain may lead to homeostatic dysregulation in this system.

The purpose of this pilot study was to evaluate the pattern and amplitude of neural activity associated with acute pain in a sample of chronic pancreatitis patients that have been using opiates daily for 6 or more months. Chronic pancreatitis is a particularly intransigent condition associated with visceral pain. Similar to other chronic pain conditions, pain originates from a specific location, but over time the etiology of this pain spreads. In part, this may be due to alterations in central processing, as chronic pancreatitis is associated with changes in brain structure in pain processing regions (Bouwense et al., 2013; Dimcevski et al., 2007a, 2006; Dimcevski et al., 2007b), mimics neuropathies (Dimcevski et al., 2007a; Drewes et al., 2008; Staahl et al., 2007), and surgical intervention is not guaranteed to resolve pain symptoms (Cahen et al., 2007; Rosch et al., 2002). Given these difficulties, opiates are frequently prescribed to treat chronic pancreatitis (Goulden, 2013; Kleeff et al., 2017). Little is known, however, about the effects of chronic opiate use on the processing (behavioral and neurobiological) of acute pain in this population. Given the need to develop non-opiate based therapeutics for patients with chronic pain, evaluating the neural response to pain in these patients may elucidate potential treatment targets and inform future interventions.

Section snippets

Participants and questionnaires

All procedures for this research were reviewed and approved by the Medical University of South Carolina’s (MUSC) Institutional Review Board. Individuals with chronic non-alcoholic pancreatitis (‘patients’, n = 14, 10 female) currently using chronic opiates (>6 months) were recruited from the MUSC Pancreatitis Clinic. Non-opiate using control individuals (‘controls’, n = 14, 10 female) were recruited from the local community. Following informed consent, participants completed a demographic

Demographics and pain characteristics

No group differences in gender were revealed (10 women and 4 men in both groups), however patients were older than controls (patients 48.8 ± 8.2 years vs. controls 37.1 ± 13.2 years, p < 0.05). In comparison to the control group, the patient group had significantly higher scores on the BPI, including subscales for current (patients 3.4 ± 3.4 vs. controls 0.2 ± 0.8) and average pain (patients 5.1 ± 2.3 vs. controls 0.8 ± 1.2; p’s<.005; Supplementary Table S1 for details). No group differences in

Summary

While acute opiate usage is associated with acute pain relief, chronic opiate usage leads to a sensitized behavioral response to pain. Acute pain leads to elevated activity in a network of neural regions (e.g., the ACC, insula, and thalamus) that also have high opiate receptor concentrations. Very little is known, however, about the effects of chronic opiate usage on the brain response to acute pain. This study is the first to demonstrate that a dose of opiates that normalizes the behavioral

Conclusion

Individuals using chronic prescription opiates for pain have elevated neural responses to a thermal pain stimulus relative to healthy controls. The amount of opiates used, as measured by morphine milligram equivalents, is positively associated with larger brain responses to pain. These findings need to be explored in a larger sample and over a longer period of time to determine whether and how chronic opiate usage may increase risk for conversion to nonmedical prescription opioid use, opioid

Role of funding source

This work was supported by F31DA043330 (Dowdle), R21DA044503 (Hanlon), R25DA020537 (Back and Brady), K02 DA039229 (Back), R01DA038971 (Borckardt).

Contributors

L.D. performed preprocessing, analyses, produced the figures and wrote the manuscript, J.B. designed the study, acquired data and contributed to manuscript preparation, S.B. contributed to interpreting the data and manuscript preparation, C.H. contributed to interpreting the data and manuscript preparation. All authors have approved the final manuscript.

Conflict of interest

No conflict declared.

Acknowledgements

The authors would like to thank the Center for Biomedical Imaging for their support.

References (70)

  • E.E. Ewan et al.

    Analgesics as reinforcers with chronic pain: evidence from operant studies

    Neurosci. Lett.

    (2013)
  • F. Fregni et al.

    Clinical effects and brain metabolic correlates in non-invasive cortical neuromodulation for visceral pain

    Eur. J. Pain

    (2011)
  • W.H. Lyness et al.

    Morphine self-administration in the rat during adjuvant-induced arthritis

    Life Sci.

    (1989)
  • E.A. Mayer et al.

    Differences in brain responses to visceral pain between patients with irritable bowel syndrome and ulcerative colitis

    Pain

    (2005)
  • V. Mitsi et al.

    Modulation of pain, nociception, and analgesia by the brain reward center

    Neuroscience

    (2016)
  • E. Navratilova et al.

    Brain circuits encoding reward from pain relief

    Trends Neurosci.

    (2015)
  • P. Petrovic et al.

    Brainstem involvement in the initial response to pain

    Neuroimage

    (2004)
  • L.A. Roeckel et al.

    Opioid-induced hyperalgesia: cellular and molecular mechanisms

    Neuroscience

    (2016)
  • M.D. Sanna et al.

    Regionally selective activation of ERK and JNK in morphine paradoxical hyperalgesia: a step toward improving opioid pain therapy

    Neuropharmacology

    (2014)
  • T. Sprenger et al.

    Opioidergic activation in the medial pain system after heat pain

    Pain

    (2006)
  • R. Tanasescu et al.

    Functional reorganisation in chronic pain and neural correlates of pain sensitisation: a coordinate based meta-analysis of 266 cutaneous pain fMRI studies

    Neurosci. Biobehav. Rev.

    (2016)
  • L. Wu et al.

    The efficacy of N-methyl-D-aspartate receptor antagonists on improving the postoperative pain intensity and satisfaction after remifentanil-based anesthesia in adults: a meta-analysis

    J. Clin. Anesth.

    (2015)
  • M.S. Angst et al.

    Opioid-induced hyperalgesia: a qualitative systematic review

    Anesthesiology

    (2006)
  • K.S. Barth et al.

    Pain and motives for use among non-treatment seeking individuals with prescription opioid dependence

    Am. J. Addict.

    (2013)
  • S.A. Bouwense et al.

    Altered central pain processing after pancreatic surgery for chronic pancreatitis

    Br. J. Surg.

    (2013)
  • D.L. Cahen et al.

    Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis

    N. Engl. J. Med.

    (2007)
  • V.D. Calhoun et al.

    The impact of T1 versus EPI spatial normalization templates for fMRI data analyses

    Hum. Brain Mapp.

    (2017)
  • F. Cauda et al.

    Massive modulation of brain areas after mechanical pain stimulation: a time-resolved fMRI study

    Cereb. Cortex

    (2014)
  • C.S. Cleeland et al.

    Pain assessment: global use of the brief pain inventory

    Ann. Acad. Med. Singap.

    (1994)
  • G. Corder et al.

    Endogenous and exogenous opioids in pain

    Annu. Rev. Neurosci.

    (2018)
  • G. Dimcevski et al.

    Hypoalgesia to experimental visceral and somatic stimulation in painful chronic pancreatitis

    Eur. J. Gastroenterol. Hepatol.

    (2006)
  • G. Dimcevski et al.

    Assessment of experimental pain from skin, muscle, and esophagus in patients with chronic pancreatitis

    Pancreas

    (2007)
  • R. Drdla et al.

    Induction of synaptic long-term potentiation after opioid withdrawal

    Science

    (2009)
  • A.M. Drewes et al.

    Pain in chronic pancreatitis: the role of neuropathic pain mechanisms

    Gut

    (2008)
  • P. Flodin et al.

    Intrinsic brain connectivity in chronic pain: a resting-state fMRI study in patients with rheumatoid arthritis

    Front. Hum. Neurosci.

    (2016)
  • Cited by (4)

    • Transcranial magnetic stimulation, deep brain stimulation, and other forms of neuromodulation for substance use disorders: Review of modalities and implications for treatment

      2020, Journal of the Neurological Sciences
      Citation Excerpt :

      When this depolarizing current is strong enough, however, it leads to a cascade of neurotransmitter release, excitatory postsynaptic potentials, and eventually action potentials in neurons receiving monosynaptic inputs from the neurons depolarized by the TMS pulse. This has been documented using interleaved TMS/BOLD imaging wherein a single pulse of TMS induces an elevation in the BOLD signal in the vicinity of the TMS coil and in monosynaptic target regions [37,38]. In this manner, cortical pulses of TMS can be used to investigate frontal-striatal connectivity, as the dorsal and ventral striatum both receive monosynaptic inputs from the frontal cortex.

    View full text