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How Can Neuromodulation Help Opioid Addiction Patients?

June 23rd, 2021

The opioid crisis is one of the most alarming, increasingly widespread public health risks in our global society. It is most concentrated in the United States, where the percentage of the population abusing opioid drugs (6%) is highest [1].

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Opioid analgesics (opioids) are medications commonly used in the treatment of moderate to severe chronic pain. 

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We’ve all experienced pain; the unpleasant sensation produced by processes that either damage or are capable of damaging your body’s tissues. However, for some, pain is an inescapable part of their day-to-day lives. For these individuals, their pain is defined as chronic pain, meaning pain that persists for a period of three months or longer. Chronic pain can occur for a range of reasons, including fibromyalgia, neck or lower back disorders, arthritis, neuropathies, and cancer. 

 

According to current estimates, around 1 in 5, or more than 1.5 billion people globally, suffer from chronic pain [2]. In the UK alone, it is estimated to affect more than two fifths of the population, or around 28 million adults [3]. Of the 43% of the UK population that experience chronic pain, up to 14.3% are living with chronic pain that is either moderately or severely disabling [3]. It can have a significant impact on an individual’s quality of life by impacting their mood, sleep quality, mobility, social interaction, and ability to work. In fact, around half of those who experience chronic pain suffer from depression, and two thirds are unable to work [4]. This is mirrored in the US where 2012 figures suggested that the value of lost productivity due to chronic pain equals as much as $335 billion annually [5].

 

Therefore for those living with chronic pain, opioids can be a vital lifeline without which they would struggle to function. Every rose has its thorn, however, and opioids are no different; their use is associated with several problems including misuse, addiction, overdose and developing tolerance.

 

And it is these problems that have facilitated the growth of the opioid epidemic.

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The Origins Of The Opioid Crisis

The origins of the opioid crisis date back to 1990, when Dr. Mitchell Max, the President of the American Pain Society, wrote an editorial in Annals of Internal Medicine calling for a different approach to pain management in light of the lack of improvements in pain assessment and treatment over the last 20 years [6]. Dr. Max pushed the conventional wisdom of the day that the therapeutic use of opioids rarely results in addiction, although this wisdom was founded on a single publication which lacks significant detail around the study’s methodology [7].

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The American Pain Society consequently released quality assurance standards for pain relief aligned with Dr. Max’s recommendation [8] which influenced the opinion of physicians towards pain. Pain was soon considered to be a ‘fifth vital sign’ which therefore should be treated with a similar level of concern. This led to well-intentioned efforts by healthcare professionals to improve pain management for their patients. 

 

Concurrently, pharmaceutical companies were capitalising on the paradigm shift by aggressively marketing new prescription opioids, the first of which, oxycodone (OxyContinⓇ), was released in 1996 by Purdue Pharma. Infamously, Purdue were later found to have misrepresented the risk of addiction posed by the drug in these marketing campaigns [9].

 

These two factors coincided to lay the foundations of the crippling opioid crisis we see today. Between 1997 and 2002, prescriptions issued for oxycodone had increased tenfold from 670,000 to over 6.2 million per year [9].

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The Opiod Crisis Today

So once these foundations had been laid, the dangers which opioids posed to patients in terms of developing tolerance, misuse and addiction, were fuel to the fire, allowing the epidemic to spread dramatically.

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Opioid misuse can be defined as opioid use in any way that is: not directed by a prescriber, without a prescription of one’s own, or taking them in greater amounts, more often or longer than directed. Opioid addiction is characterised by intense cravings and the compulsive use of opioids for reasons other than medical.

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It’s currently estimated that around 20-30% of those who are prescribed opioids for chronic pain will misuse them [10]. This translates into 10.3 million people in the US having misused opioids in 2018; of these, 9.9 million misused prescription painkillers and 808,000 used heroin [10]. Of those who misuse painkillers, around 10% later become addicted to them [10]. A more shocking statistic still is that 80% of those who use heroin first misused prescription opioids [11].

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Opioid misuse and addiction often leads to overdose and death as a result of respiratory depression. It is estimated that, of the 0.5 million deaths globally attributable to drug use annually, 70% are related to opioids, and more than 30% of these deaths are caused by overdose [12]. In the UK, overdoses from opioid painkillers surged to 20,130 cases in 2017, a rise of 85% in the past decade [13]. In the US, the number of deaths caused by opioid overdoses rose from 47,000 in 2017 to nearly 50,000 in 2019 [14]. Globally, the number of people that died from an opioid overdose increased by 120% between 2010 and 2018 [12].

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These ever-growing figures on the human toll are even more alarming when you consider that medical guidelines in both countries have somewhat revoked recommendations for prescribing opioids for chronic pain management. NICE guidelines in the UK now state that, “there is little evidence that opioids are helpful for chronic pain.” [15] In the US, efforts to curb the use of opioids have led to a decrease in the number of prescriptions from 244 million in 2009 to 153 million in 2019 [16]. 

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It therefore becomes apparent upon analysis that despite a reduction in their prescription, we continue to see a rise in opioid misuse and overdose death toll. This is indicative of how deep the roots of the opioid crisis have and will continue to run in our societies unless there is a concerted effort to both tackle the social determinants of health (SDOH) which surround opioid addiction, and also innovate opioid withdrawal and chronic pain treatments. 

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The Role of Neuromodulation

Neuromodulation has an important role to play in helping to control this crisis. The International Neuromodulation Society defines therapeutic neuromodulation as “the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation… to specific neurological sites in the body.” [17] 

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So, how can it help?

As An Alternative To Opioid Prescription

The symptoms of opioid withdrawal are a huge barrier to recovery from opioid addiction. They can range from yawning, watery eyes, runny nose and diarrhea to vomiting, anxiety, body aches, sweating, hallucinations and seizures.

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Depending on the half-life of the opioid, these symptoms will generally resolve after 5-14 days, but the distress caused in the first few days of abstinence can be so severe that many patients are unable to complete discontinuation as avoiding the withdrawal symptoms becomes the most powerful driving force behind continued use [29].

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Some supportive pharmacological treatments exist to alleviate uncomfortable symptoms associated with acute detoxification, such as clonidine, baclofen, ibuprofen, and lofexidine, but their overall effectiveness is not found to be sufficient [30]. And while medications such as benzodiazepines may be more effective, serious concerns exist around the fact they can be additive and contribute to severe respiratory suppression [31].

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Attention has therefore turned towards the exploration of novel non-pharmacological interventions to alleviate the symptoms of opioid withdrawal. Four electrical nerve stimulators have received FDA-approval for the adjunct treatment of acute withdrawal symptoms. All four devices harness auricular neuromodulation; are placed behind the ear to stimulate cranial nerves V, VII, IX and X with auricular projections. The effect is a prompt alleviation of the withdrawal symptoms associated with acute discontinuation of opioid use [32].

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While three of these devices (DyAnsys’ DrugRelief®, IHS’ NSS-2 Bridge and Soterix Medical’s electro-detox™) apply percutaneous electrical nerve field stimulation (PENS), delivering electrical stimulation through acupuncture-style needles in the skin, the fourth and most recently approved device, Spark Biomedical’s Sparrow Therapy System, applies transcutaneous auricular neurostimulation (tAN™) completely non-invasively.

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A number of studies suggest that the main pathophysiological basis for the mechanisms of action of these devices may relate to transcutaneous auricular vagus nerve stimulation (taVNS) and the resulting impact on sympathetic and parasympathetic nervous system outflows [33,34]. These studies indicate that taVNS alters the balance towards parasympathetic predominance which can be beneficial in many conditions characterised by increased sympathetic activity [32,35].

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Conclusion

In conclusion, despite efforts to reduce opioid prescriptions in the UK and US as a treatment for chronic pain, misuse, addiction and overdose death rates related to opioids continue to rise. Neuromodulation shows potential for making an impact on efforts to curb the epidemic. As a drug-free alternative treatment option for chronic pain, certain forms of neuromodulation (SCS and nVNS) are already available as supplements to opioids, and clinical evidence continues to amass for the potential of other forms (e.g. TENS, tDCS) to help relieve chronic pain in an even wider range of conditions. Innovation also continues into neuromodulation devices for the treatment of opioid withdrawal symptoms, where this technology can help to remove the largest barrier to complete discontinuation in many patients.

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To Treat Opioid Withdrawal Symptoms

The first neuromodulation device for pain relief was implanted in 1967, so the use of this technology to manage chronic pain is not a novel idea. Different levels of clinical evidence exist for various forms of neuromodulation across numerous conditions; from FDA-approved to preclinical.

 

Today, spinal cord stimulation (SCS) is a form of neuromodulation commonly used in the treatment of failed back surgery syndrome (FBSS) [18,19], complex regional pain syndrome (CRPS) [18,19], diabetic neuropathy [20], and peripheral artery disease [21]. In SCS, a small generator device is implanted under the skin with a very thin lead placed in the epidural space outside the spine where electrical impulses are sent to alleviate pain.

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Another example is the non-invasive application of vagus nerve stimulation (nVNS) in the treatment of migraines and cluster headaches [22].

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Clinical evidence continues to amass for the potential efficacy of transcutaneous electrical nerve stimulation (TENS) [23,24] and transcranial direct current stimulation (tDCS) [25,26,27] in treating chronic back and limb pain as well as post-surgical pain.

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This therefore suggests that there is potential for neuromodulation to replace or supplement opioids in the management of multiple chronic pain conditions. Despite this, their relative novelty and the initial costs of implanted devices mean that these treatments have typically only been offered to patients as a last resort, after they have tried the more conventional options of medications, physical therapy and surgery. However, clinical preference and insurance coverage is changing, meaning neuromodulation is now being considered much earlier in treatment planning [28]. 

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By providing an alternative, effective and safer therapeutic intervention, this could be key to closing the gateway to addiction and misuse that opioid prescriptions for chronic pain often become.

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References

  1. Bergen-Cico D, Scholl S, Ivanashvili N, et al. Opioid Prescription Drug Abuse and Its Relation to Heroin Trends [Internet]. Neuropathol. Drug Addict. Subst. Misuse. Elsevier Inc.; 2016. Available from: http://dx.doi.org/10.1016/B978-0-12-800213-1.00082-1.

  2. Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public Health. 2011;11:770.

  3. Fayaz A, Croft P, Langford RM, et al. Prevalence of chronic pain in the UK: a systematic review and meta-analysis of population studies. BMJ Open [Internet]. 2016;6:e010364. Available from: http://bmjopen.bmj.com/content/6/6/e010364.abstract.

  4. NICE. NATIONAL INSTITUTE FOR HEALTH AND CARE Guideline scope Chronic pain : assessment and management. 2018;1–10.

  5. Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain. 2012;13(8):715-724. doi:10.1016/j.jpain.2012.03.009

  6. Max MB. Improving outcomes of analgesic treatment: is education enough? Ann Intern Med. 1990 Dec 1;113(11):885-9. 

  7. Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med. 1980;302:123. 

  8. Max MB. American Pain Society quality assurance standards for relief of acute pain and cancer pain. Bond MR, Charlton JE, Woolf CJ, eds. Proceedings of the VI World Congress of Pain. Amsterdam, The Netherlands: Elsevier. 1990: 186-189.

  9. Prescription Drugs: OxyContin Abuse and Diversion and Efforts to Address the Problem. Washington, DC: General Accounting Office; December 2003. Publication GAO-04-110 [Google Scholar]

  10. Substance Abuse and Mental Health Services Administration. Key substance use and mental health indicators in the United States: Results from the 2018 National Survey on Drug Use and Health. HHS Publ. No. PEP19-5068, NSDUH Ser. H-54 [Internet]. 2019;170:51–58. Available from: https://www.samhsa.gov/data/.

  11. Muhuri PK, Gfroerer JC, Davies MC. Associations of Nonmedical Pain Reliever Use and Initiation of Heroin Use in the United States. CBHSQ Data Rev. August 2013.

  12. WHO. Fact sheet on Opioid overdose. 2020; Available from: https://www.who.int/news-room/fact-sheets/detail/opioid-overdose.

  13. The opioid timebomb [Internet]. Available from: https://assets.standard.co.uk/opioids/index.html#group-or-appendices-32zWpperPw.

  14. CDC/NCHS, National Vital Statistics System, Mortality. CDC WONDER, Atlanta, GA: US Department of Health and Human Services, CDC; 2019. https://wonder.cdc.gov.

  15. NICE Guidance. Medicines optimisation in chronic pain. Available from: https://www.nice.org.uk/advice/ktt21/chapter/Evidence-context#opioid-medicines-in-chronic-pain

  16. Hedegaard H, Miniño AM, Warner M. Drug Overdose Deaths in the United States, 1999-2018. NCHS Data Brief. 2020;1–8.

  17. The International Neuromodulation Society. Available from: https://www.neuromodulation.com/

  18. North RB, Kidd DH, Farrokhi F, et al. Spinal cord stimulation versus repeated lumbosacral spine surgery for chronic pain: A randomized, controlled trial. Neurosurgery. 2005;56:98–106.

  19. Kemler MA, Barendse GA, van Kleef M, et al. Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N. Engl. J. Med. [Internet]. 2000;343:618–624. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10965008.

  20. Slangen R, Schaper NC, Faber CG, et al. Spinal Cord Stimulation and Pain Relief in Painful Diabetic Peripheral Neuropathy: A Prospective Two-Center Randomized Controlled Trial. Diabetes Care [Internet]. 2014;DC_140684. Available from: http://care.diabetesjournals.org/content/early/2014/09/09/dc14-0684.abstract.

  21. Horsch S, Claeys L. Epidural spinal cord stimulation in the treatment of severe peripheral arterial  occlusive disease. Ann. Vasc. Surg. 1994;8:468–474.

  22. ElectroCore. GammaCore: Instructions for Use for GammaCore. 2016.

  23. Pivec R, Minshall ME, Mistry JB, et al. Decreased Opioid Utilization and Cost at One Year in Chronic Low Back Pain Patients  Treated with Transcutaneous Electric Nerve Stimulation (TENS). Surg. Technol. Int. 2015;27:268–274.

  24. Erdogan M, Erdogan A, Erbil N, et al. Prospective, Randomized, Placebo-controlled Study of the Effect of TENS on  postthoracotomy pain and pulmonary function. World J. Surg. 2005;29:1563–1570.

  25. Stamenkovic DM, Mladenovic K, Rancic N, et al. Effect of Transcranial Direct Current Stimulation Combined With Patient-Controlled  Intravenous Morphine Analgesia on Analgesic Use and Post-Thoracotomy Pain. A Prospective, Randomized, Double-Blind, Sham-Controlled, Proof-of-Concept Clinical Trial. Front. Pharmacol. 2020;11:125.

  26. Borckardt JJ, Reeves ST, Robinson SM, et al. Transcranial Direct Current Stimulation (tDCS) Reduces Postsurgical Opioid Consumption in Total Knee Arthroplasty (TKA). Clin. J. Pain [Internet]. 2013;29. Available from: https://journals.lww.com/clinicalpain/Fulltext/2013/11000/Transcranial_Direct_Current_Stimulation__tDCS_.1.aspx.

  27. Khedr EM, Sharkawy ESA, Attia AMA, et al. Role of transcranial direct current stimulation on reduction of postsurgical opioid consumption and pain in total knee arthroplasty: Double randomized clinical trial. Eur. J. Pain [Internet]. 2017;21:1355–1365. Available from: https://doi.org/10.1002/ejp.1034.

  28. Pain and neuromodulation: What’s all the “buzz” about? Harvard Health Publishing. March 2020. Available from: https://www.health.harvard.edu/blog/pain-and-neuromodulation-whats-all-the-buzz-about-2020030318975

  29. Cicero TJ, Ellis MS. The prescription opioid epidemic: a review of qualitative studies on the progression from initial use to abuse. Dialogues Clin Neurosci. 2017;19(3):259-269. doi:10.31887/DCNS.2017.19.3/tcicero

  30. Hermann D, Klages E, Welzel H, Mann K, Croissant B. Low efficacy of non-opioid drugs in opioid withdrawal symptoms. Addict Biol. 2005;10(2):165-169. doi:10.1080/13556210500123514

  31. Lintzeris N, Nielsen S. Benzodiazepines, methadone and buprenorphine: interactions and clinical management. Am J Addict. 2010;19(1):59-72. doi:10.1111/j.1521-0391.2009.00007.x

  32. Qureshi, I.S., Datta-Chaudhuri, T., Tracey, K.J. et al. Auricular neural stimulation as a new non-invasive treatment for opioid detoxification. Bioelectron Med 6, 7 (2020). https://doi.org/10.1186/s42234-020-00044-6

  33. Clancy JA, Mary DA, Witte KK, Greenwood JP, Deuchars SA, Deuchars J. Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimul. 2014;7(6):871-877. doi:10.1016/j.brs.2014.07.031

  34. Deuchars SA, Lall VK, Clancy J, et al. Mechanisms underpinning sympathetic nervous activity and its modulation using transcutaneous vagus nerve stimulation. Exp Physiol. 2018;103(3):326-331. doi:10.1113/EP086433

  35. Hong GS, Zillekens A, Schneiker B, et al. Non-invasive transcutaneous auricular vagus nerve stimulation prevents postoperative ileus and endotoxemia in mice. Neurogastroenterol Motil. 2019;31(3):e13501. doi:10.1111/nmo.13501

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