Full length articleSensitized brain response to acute pain in patients using prescription opiates for chronic pain: A pilot study
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)
- et al.
Human brain mechanisms of pain perception and regulation in health and disease
Eur. J. Pain
(2005) - et al.
Brain mediators of the effects of noxious heat on pain
Pain
(2014) - et al.
High opiate receptor binding potential in the human lateral pain system
Neuroimage
(2006) - et al.
Cerebral interactions of pain and reward and their relevance for chronic pain
Neurosci. Lett.
(2012) - et al.
A component based noise correction method (CompCor) for BOLD and perfusion based fMRI
Neuroimage
(2007) - et al.
Development and validation of the current opioid misuse measure
Pain
(2007) - et al.
Further evidence validating adjuvant arthritis as an experimental model of chronic pain in the rat
Life Sci.
(1982) - et al.
Opiate self-administration as a measure of chronic nociceptive pain in arthritic rats
Pain
(2001) - et al.
Pain in chronic pancreatitis: the role of reorganization in the central nervous system
Gastroenterology
(2007) - et al.
Common brain mechanisms of chronic pain and addiction
Neuron
(2016)
Analgesics as reinforcers with chronic pain: evidence from operant studies
Neurosci. Lett.
Clinical effects and brain metabolic correlates in non-invasive cortical neuromodulation for visceral pain
Eur. J. Pain
Morphine self-administration in the rat during adjuvant-induced arthritis
Life Sci.
Differences in brain responses to visceral pain between patients with irritable bowel syndrome and ulcerative colitis
Pain
Modulation of pain, nociception, and analgesia by the brain reward center
Neuroscience
Brain circuits encoding reward from pain relief
Trends Neurosci.
Brainstem involvement in the initial response to pain
Neuroimage
Opioid-induced hyperalgesia: cellular and molecular mechanisms
Neuroscience
Regionally selective activation of ERK and JNK in morphine paradoxical hyperalgesia: a step toward improving opioid pain therapy
Neuropharmacology
Opioidergic activation in the medial pain system after heat pain
Pain
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.
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.
Opioid-induced hyperalgesia: a qualitative systematic review
Anesthesiology
Pain and motives for use among non-treatment seeking individuals with prescription opioid dependence
Am. J. Addict.
Altered central pain processing after pancreatic surgery for chronic pancreatitis
Br. J. Surg.
Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis
N. Engl. J. Med.
The impact of T1 versus EPI spatial normalization templates for fMRI data analyses
Hum. Brain Mapp.
Massive modulation of brain areas after mechanical pain stimulation: a time-resolved fMRI study
Cereb. Cortex
Pain assessment: global use of the brief pain inventory
Ann. Acad. Med. Singap.
Endogenous and exogenous opioids in pain
Annu. Rev. Neurosci.
Hypoalgesia to experimental visceral and somatic stimulation in painful chronic pancreatitis
Eur. J. Gastroenterol. Hepatol.
Assessment of experimental pain from skin, muscle, and esophagus in patients with chronic pancreatitis
Pancreas
Induction of synaptic long-term potentiation after opioid withdrawal
Science
Pain in chronic pancreatitis: the role of neuropathic pain mechanisms
Gut
Intrinsic brain connectivity in chronic pain: a resting-state fMRI study in patients with rheumatoid arthritis
Front. Hum. Neurosci.
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 SciencesCitation 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.
Spinal Cord Resting State Activity in Individuals With Fibromyalgia Who Take Opioids
2021, Frontiers in Neurology