It is estimated that 10% of chronic pain patients abuse their opiate prescriptions, with serious consequences to neurotransmitter levels

Opioid Addiction and Neurotransmitter Balance

Posted Ramona Richard, MS, NC Blog

Options for relief from chronic pain are a highly sought after commodity among pharmaceutical companies and patients. Unlike acute short-term pain, chronic pain is caused by the central nervous system (CNS) perceiving pain with or without peripheral input.[1] Sufferers of chronic pain are often prescribed opiates to alleviate discomfort. Opiates are a class of pain-relief drugs from opium extracted from poppy (Papaver somniferum) seeds.[2] Opium derivatives have been used for hundreds of years to treat pain.[3] Hospitals commonly use morphine, the most active ingredient of opium, to treat chronic or acute pain.[4] Other opiates such as hydrocodone, oxycodone, and tramadol are commonly prescribed to patients to aid in managing chronic pain. It is estimated, however, that 10% of chronic pain patients abuse their opiate prescriptions, and this percentage continues to rise.[5] Another member of the opioid family is heroin, the most common illicit drug, which is made by deacetylation of morphine.[6] At least 80% of heroin addicts were first introduced to opioids in the form of pharmaceuticals.[7] Use of non-prescription opioids by opioid addicted individuals costs $72.5 billion annually.[8] Opioids should be used with extreme caution to avoid dependency and addiction.

Opioid Receptors

The human body has natural opioidergic neurotransmission, which is normally under the influence of beta-endorphins.[9] Opioid receptors diminish the sensation of pain, which is an important bodily function as studies have shown that chronic pain can stress the body even to the point of death.[10] Opioid receptors are mostly found in the nervous system, but are also located on many peripheral organs.[11] There are several types of opioid receptors, the most common of which for exogenous substances to act on is the μ, or MOR receptor.[12] These receptors have been found to influence the HPA-axis, an essential regulator of the neuroendocrine system.[13] Morphine, perhaps the most commonly studied opiate, activates MOR receptors which in turn modulate dopamine receptors in the brain.[14] Activation of these central dopamine reward pathways creates a euphoric feeling or “high”, sought after for pain relief or recreation.[15] Morphine can also increase serotonin release (an inhibitory neurotransmitter) and decrease norepinephrine release (an excitatory neurotransmitter).[16] This upregulation of the “feel-good neurotransmitters” and downregulation of a “stress neurotransmitter” is, in terms of the HPA axis, why opioid use can so easily lead to addiction and dependence.

Opioids, Dopamine, and Reward

Opioid use activates areas of the brain responsible for reward-processing while downregulating areas responsible for attention and cognitive function.[17] Because opioids act on dopamine, they influence salience, or the ability of the brain to desire a rewarding stimulus. Opiates are actually so influential on salience that opioid-addicted individuals have been shown to release dopamine upon the sound of a pill bottle or the sight of a prescription slip.[18] It is very common to develop opioid tolerance in which the dosage must continue to increase in order to maintain pain alleviation.[19] Over time, opioid use will diminish the release of dopamine induced by typical stimuli (eating, romance, gifts) and addicts will only feel salience toward the opioid and stimuli associated with the opioid.[20] Sufferers of opioid addiction often confuse their addiction with pain relief, but the body and neuroendocrine system are affected by pharmaceutical opioid use and recreational or illicit opioid use in the same way.[21] Addiction is characterized not only by the biochemical dependence on opioids, but also by social and emotional turbulence caused by prioritization of drugs.[22]

Opioid Addiction & HPA Axis

Long-term morphine use increases pro-inflammatory cytokine levels, in turn upregulating NMDA receptors (essential for binding to the excitatory neurotransmitter glutamate), which then reduces GABA levels (a neurotransmitter responsible for promoting calm and good mood).[23]  Opioids also upregulate GABA’s interaction with serotonin neurons, which results in decreased serotonin activity during withdrawal, meaning that serotonin levels deplete.[24] Withdrawal also causes hyperactivity of norepinephrine[25], resulting in anxiety and increased stress. This increased stress response in combination with low dopamine, serotonin, and GABA makes the withdrawal process horrible for addicted individuals. It is estimated that 3-16% of the population is genetically predisposed to addiction, but even without predisposition, the disruption in HPA-axis balance stemming from long-term opioid use is a perfect recipe for development of an addiction.[26] Methadone is a common treatment for opioid addiction as it prevents further dopamine desensitization in the brain.[27] Methadone is almost completely detoxified by the body and has a much longer half-life than other opioids (meaning the short-term, intense “high” produced by other opioids is stifled), so its therapeutic use can be highly effective.[28] Treatment of opioid addiction can be a painful and long process, but is exceptionally rewarding if successful.

Opioid addiction can occur with the use of illegal drugs, non-prescription pharmaceuticals, and with prescribed opioids for pain management. Due to the highly addictive nature and biochemical mechanism of action of opioids, it is wise to be weary of any substance containing opioidergically active compounds. Taking opioids as prescribed can be life-saving and provide great relief to patients, but it is important for practitioners and patients alike to keep in mind potential outcomes of opioid addiction and the long-term effects that all opioids have on the body.

[1] Garland, E. L., Froeliger, B., Zeidan, F., Partin, K., & Howard, M. O. (2013). The downward spiral of chronic pain, prescription opioid misuse, and addiction: Cognitive, affective, and neuropsychopharmacologic pathways. Neuroscience & Biobehavioral Reviews, 37(10), 2597-2607. doi:10.1016/j.neubiorev.2013.08.006
[2] Merrer, J. L., Becker, J. A. J., Befort, K., & Kieffer, B. L. (2009). Reward Processing by the Opioid System in the Brain. Physiological Reviews, 89(4), 1379–1412.
[3] Walwyn, W. M., Miotto, K. A., & Evans, C. J. (2010). Opioid pharmaceuticals and addiction: The issues, and research directions seeking solutions. Drug and Alcohol Dependence, 108(3), 156–165.
[4] Merrer, op. cit.
[5] Garland, op. cit.
[6] Merrer, op. cit.
[7] Written by Nicole Makris | Published on February 26, 2016. (2016, February 26). Prescription Drugs Are Leading to Heroin Addictions. Retrieved April 07, 2017, from
[8] Katz, N. P., Birnbaum, H., Brennan, M. J., Freedman, J. D., Gilmore, G. P., Jay, D., … White, A. G. (2013). Prescription Opioid Abuse: Challenges and Opportunities for Payers. The American Journal of Managed Care, 19(4), 295–302.
[9] Garland, op. cit.
[10] Walwyn, op. cit.
[11] Feng, Y., He, X., Yang, Y., Chao, D., Lazarus, L. H., & Xia, Y. (2012). Current Research on Opioid Receptor Function. Current Drug Targets, 13(2), 230–246.
[12] Al-Hasani, R., & Bruchas, M. R. (2011). Molecular Mechanisms of Opioid Receptor-Dependent Signaling and Behavior. Anesthesiology, 115(6), 1363–1381.
[13] Lutz, P.-E., & Kieffer, B. L. (2013). Opioid receptors: distinct roles in mood disorders. Trends in Neurosciences, 36(3), 195–206.
[14] Merrer, op. cit.
[15] Al-Hasani, op. cit.
[16] Lutz, op. cit.
[17] Garland, op. cit.
[18] Garland, Ibid.
[19] Al-Hasani, op. cit.
[20] Garland, op. cit.
[21] Walwyn, op. cit.
[22] Written by Nicole Makris, op. cit.
[23] Hutchinson, M. R., Shavit, Y., Grace, P. M., Rice, K. C., Maier, S. F., & Watkins, L. R. (2011). Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia. Pharmacological Reviews, 63(3), 772–810.
[24] Lutz, op. cit.
[25] Lutz, Ibid.
[26] Walwyn, op. cit.
[27] Katz, op. cit.
[28] Kreek, M. J., Borg, L., Ducat, E., & Ray, B. (2010). Pharmacotherapy in the Treatment of Addiction: Methadone. Journal of Addictive Diseases, 29(2), 200–216.

Clinical Contributor

Sophie Thompson

Sophie Thompson

Clinical Support Intern at Sanesco Health
Sophie recently obtained her degree in Biology from UNCA in Asheville. Born and raised in Asheville, her hobbies include painting, writing and spending quality time with her dog and her family.
Sophie Thompson

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    Disclaimer: The information provided is only intended to be general educational information to the public. It does not constitute medical advice. If you have specific questions about any medical matter or if you are suffering from any medical condition, you should consult your doctor or other professional healthcare provider.