Non-opioid Drugs and Methods for Pain Control

Treating acute pain before it develops into chronic pain may be the key to preventing chronic pain from arising in the first place.

Nearly 1 billion people worldwide, or 1 in 5 adults, suffer from chronic pain that interferes with daily function.1,2 Because few effective options exist for treating chronic pain, physicians frequently prescribe strong opioids, which in the United States has resulted in an opioid abuse epidemic.1,3

Although opioids may provide short-term pain relief, they are poorly effective in the long run. Opioids block neurotransmitter release at on nociceptors.1 Tolerance develops over time, leading to dose escalation; higher doses trigger the release of inflammatory cytokines from glial cells, inducing hyperalgesia.4

A review article recently published in Nature discusses several different non-opioid drugs and methods for pain control that are currently being investigated.1 


James Zadina, MD, of Tulane University and colleagues are investigating endomorphin analogs as an alternative to opioid agents for pain control.Endogenous endomorphins relieve pain by binding to the μ-opioid receptor, but unlike opioids, endomorphins selectively induce analgesia with few side effects.

One of the endomorphin analogs evaluated showed particularly promising results: it had reduced or no addiction potential tolerance, hyperalgesia, and respiratory depression in animal models.5 Zadina and colleagues plan to continue to study this compound in clinical trials.1 

Spinal cord stimulation

Recent advances in spinal cord stimulation (SCS) technology have allowed for neuromodulation to be thought of as a viable alternative to opioids.1,2 Stimulation of dorsal root ganglion (DRG) implicated in the development of chronic pain, has been shown to be particularly effective in treating focal pain.2,6 Although traditional SCS devices may cause uncomfortable paresthesias in some patients, high-frequency SCS (HF10, 10 kHz) achieved pain relief without paresthesias.2 HF10 has demonstrated efficacy in clinical trials and is approved for chronic intractable pain of the trunk or limbs.2,7,8 Closed-loop SCS offers another promising technology currently evaluated in clinical trials.1,9 The device detects real-time changes in nociceptive signals from the target nerve and adjusts its stimulation to maintain a therapeutic dose.


“Psychotherapy has been shown to play a major role in treating chronic pain,” said Joel Katz, PhD of York University in Canada, in an interview with Clinical Pain Advisor. Several forms of psychotherapy have been shown to be effective: Cognitive Behavior Therapy (CBT), Mindfulness-based Stress Reduction (MBSR), and Acceptance and Commitment Therapy (ACT). “Even though the main objective of these forms of psychotherapy is not to reduce the intensity of pain but to improve quality-of-life, coping, and in general to contribute to a more meaningful life, pain intensity may also improve,” he added.

Treating acute pain before it develops into chronic pain may be the key to preventing chronic pain from arising in the first place.10 “Self-rated health, anxiety, expectations of recovery, depression, and resilience appear to be important predictors for chronic pain. Some of these may be changeable with targeted education and psychological input,” Marc Russo, MD of Hunter Pain Clinic in Australia, told Clinical Pain Advisor.

Patients who have depression, pre-existing pain, or severe acute pain are at risk for chronic pain due to nervous system sensitization.1,11,12 Achieving total or near-total pain relief in high-risk patients within the first 24 hours of an acute pain event may help prevent the transition to chronic pain.1

Psychotherapy may also play an important role in chronic pain prevention. Toronto General Hospital in Canada was the first medical center to use targeted psychotherapy in postsurgical patients at risk for chronic pain.1 Although published data are not available at this time, Dr Katz and researchers at the hospital report promising results.

Related Articles


1. Crow JM. Biomedicine: Move over, morphine. Nature. 2016;535(7611):S4-6.

2. Verrills P, Sinclair C, Barnard A. A review of spinal cord stimulation systems for chronic pain. J Pain Res. 2016;9:481-92.

3. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain–United States, 2016. JAMA. 2016;315(15):1624-45.

4. Roeckel L-A, Le Coz G-M, Gavériaux-Ruff C, Simonin F. Opioid-induced hyperalgesia: Cellular and molecular mechanisms. Neuroscience. June 2016.

5. Zadina JE, Nilges MR, Morgenweck J, Zhang X, Hackler L, Fasold MB. Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine. Neuropharmacology. 2016;105:215-27.

6. Shanthanna H, Chan P, McChesney J, Paul J, Thabane L. Assessing the effectiveness of “pulse radiofrequency treatment of dorsal root ganglion” in patients with chronic lumbar radicular pain: study protocol for a randomized control trial. Trials. 2012;13:52.

7. Kapural L, Yu C, Doust MW, et al. Novel 10-kHz High-frequency Therapy (HF10 Therapy) Is Superior to Traditional Low-frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg Pain: The SENZA-RCT Randomized Controlled Trial. Anesthesiology. 2015;123(4):851-60.

8. Russo M, Verrills P, Mitchell B, Salmon J, Barnard A, Santarelli D. High Frequency Spinal Cord Stimulation at 10 kHz for the Treatment of Chronic Pain: 6-Month Australian Clinical Experience. Pain Physician. 2016;19(4):267-80.

9. Denison T, Litt B. Advancing neuromodulation through control systems: a general framework and case study in posture-responsive stimulation. Neuromodulation. 2014;17 Suppl 1:48-57.

10. Katz J, Seltzer Z. Transition from acute to chronic postsurgical pain: risk factors and protective factors.Expert Rev Neurother. 2009;9(5):723-44.

11. Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol. 2010;23(5):611-5.

12. Hermans L, Van Oosterwijck J, Goubert D, et al. Inventory of Personal Factors Influencing Conditioned Pain Modulation in Healthy People: A Systematic Literature Review. Pain Pract. 2016;16(6):758-69.

This article originally appeared on Clinical Pain Advisor