Opioid Alternatives for Chronic Pain

Fresh organic vegetables and fruits on wood table are a great opioid alternative.
Read Time 6 Minutes

Approximately 20% of adults (~50 million) in the US are affected by chronic pain, defined as pain on most days or every day in the past six months.1 In addition, an estimated 7.4% of US adults experience high-impact chronic pain, which limits life or work activities for the same duration.2 Many turn to opioids for relief. However, research shows that the extended prescription of opioids for the treatment of chronic pain has questionable benefits and significant risks, from physiologic dependence and withdrawal to depression and hormonal dysregulation to cardiovascular events and accidental overdose.3

Due to the potential medical complexity of chronic pain in individual patients, a comprehensive interdisciplinary treatment strategy that includes effective nonpharmacological approaches is important to consider. In the following video, Lisa (Perry) Portera, DC, IFMCP, discusses how the functional medicine approach helps support patients with chronic pain without the use of opioids through identifying root causes of inflammatory-mediated processes.

(Video Time: 1 minute) With over 30 years of experience in clinical practice, Dr. Portera is a passionate advocate for functional medicine and its application for patients. She has worked extensively on the development of programs related to dietary and lifestyle modifications as applied to pain syndromes.

Among a range of complementary treatments, research indicates that nutritional modifications and supporting mitochondrial health are examples of promising therapeutic interventions for chronic pain.

 Opioid Alternative – Targeting Mitochondria

Mitochondria have a variety of essential functions within neurons.4 Studies have shown that the five major mitochondrial functions (the mitochondrial energy-generating system, reactive oxygen species (ROS) generation, mitochondrial permeability transition pore, apoptotic pathways, and intracellular calcium mobilization) may play critical roles in neuropathic and inflammatory pain.5 Increased levels of inflammation and excessive oxidative stress in chronic pain patients may lead to increased mitochondrial damage and reduced function.6,7

Mitochondrial Dysfunction & Support

Although this area of pain research is relatively new, mitochondrial dysfunction has been confirmed in both chronic pain patients and in animal models of chronic pain.4,8 In animal models, ROS have been implicated in chronic pain, with enhanced ROS production potentially altering the mitochondrial genome and proteome and mitochondrial sirtuins (SIRT3) playing a role in ROS levels during neuropathic pain.9 Further, substantial data have demonstrated mitochondrial involvement in painful peripheral neuropathies evoked by chemotherapy, diabetes, and HIV.4,10 For some patients, supporting mitochondrial function may be a promising strategy to alleviate or prevent chronic pain states

As a first step in enhancing mitochondrial stability, functional medicine clinicians can prescribe the Mitochondrial Food Plan, an anti-inflammatory, low-glycemic, gluten-free, low-grain, high-quality fats approach to eating. The plan focuses on supporting healthy mitochondria with therapeutic foods that improve energy production. In addition, studies suggest that intermittent fasting routines, if appropriate for a patient’s personalized nutrition strategy, may positively impact mitochondrial quality, enhancing biogenesis, energy metabolism, and overall health.11,12 Therapeutic approaches that include exercise may also support mitochondria, promoting increased mitochondrial content, improving respiratory capacity of each mitochondrion, and reducing ROS production.13

Opioid Alternative – Nutrition

Research continues to suggest that nutrition interventions have a significant impact on pain reduction, with altered overall diets and changes in specific nutrients having the greatest effects.14,15 Some of these interventions may work by enhancing mitochondrial function, as previously discussed.

Inflammation, the Elimination Diet, & SPECIFIC CONDITIONS

There is increasing evidence that diet can contribute to systemic inflammation,16 and pain perception is commonly related to inflammatory stimulus and mediators.17 The most common food allergens in adults that may prompt allergic reactions such as inflammation include cow’s milk antigens (alpha-lactalbumin, beta-lactoglobulin, casein), wheat and wheat gluten, eggs, and soy proteins. Because food intolerances and allergies can be challenging to diagnose, and testing for these disorders is variable in terms of sensitivity and specificity, most researchers believe that elimination diets are the gold standard for diagnosis of food reactions.18-20 Encouraging wholesome eating is an essential part of chronic pain management, along with investigating possible immune reactivity to food.21

Chronic Musculoskeletal Pain

Studies suggest that anti-inflammatory Mediterranean-style diets may not only reduce risk of inflammatory arthritis22 but may also help reduce progression of symptoms. A 2023 systematic review of six cohort studies that included adults over 45 years of age with osteoarthritis found that those who followed a Mediterranean or Prudent dietary pattern reported reduced progression of their osteoarthritis symptoms while those who followed a Western dietary pattern reported an increase of symptoms.23 A small 2018 study (n=14) suggested consumption of a plant-based diet decreased pain and improved quality of life for subjects with reported chronic musculoskeletal pain.24 A 2019 study suggests that vitamin D deficiency may be associated with lower back pain.25 Supplementation with vitamin D (to sufficient serum vitamin D level) in these patients may increase mitochondrial function and inhibit muscle atrophy, according to the study authors. It may also have a beneficial impact on an effective early rehabilitation in lower back pain patients.25

Interstitial Cystitis

Studies that examine the role of diet in interstitial cystitis/bladder pain syndrome (IC/BPS) continue to evolve. Based on a 2012 review, anecdotal reports and questionnaire-based surveys suggest that in patients with IC/BPS, nearly 90% experience sensitivities to a variety of foods.26 According to the review, citrus fruits, tomatoes, vitamin C, artificial sweeteners, coffee, tea, carbonated and alcoholic beverages, and spicy foods are potential triggers that exacerbate symptoms.26 A promising report in 2017 found that intensive systematic dietary manipulation alleviated the symptoms of IC/BPS in women after three months of intervention, with continued clinical efficacy for at least one year.27 More recently, a 2019 study on bladder pain syndrome published in Primary Care reported that dietary changes (avoiding acidic, spicy, and caffeinated foods) were effective at relieving symptoms for patients.28

Fibromyalgia and Central Sensitization

Recent research suggests that oxidative stress and impaired mitochondrial functioning may be involved in the pathogenesis of fibromyalgia,29 which indicates that nutritional treatment may be a viable complementary intervention for this condition. A 2021 systematic review found that fibromyalgia patients who followed plant-based dietary patterns, such as vegetarian and vegan, showed significant improvements in biochemical parameters, pain at rest, quality of sleep, quality of life, and general health status compared to those who followed an omnivorous or Western diet.30 An older study showed that in fibromyalgia patients with celiac disease, more than one-third of patients who removed gluten from their diet were able to discontinue opioid therapy for chronic pain.31 In chronic pain patients with central sensitization, including those with whiplash, temporomandibular disorders, lower back pain, osteoarthritis, and fibromyalgia, among others, a 2014 study found that the ketogenic diet may diminish the hyper-excitability of the central nervous system.32

Research into the role of nutrition and mitochondrial support for modulating chronic pain continues to grow. How can these therapies be integrated into the functional medicine protocol for treating pain patients? Learn more at IFM’s Bioenergetics Advanced Practice Module.


  1. Yong RJ, Mullins PM, Bhattacharyya N. Prevalence of chronic pain among adults in the United States. Pain. 2022;163(2):e328-e332. doi:1097/j.pain.0000000000002291
  2. Zelaya CE, Dahlhamer JM, Lucas JW, Connor EM. Chronic pain and high-impact chronic pain among U.S. adults, 2019. NCHS Data Brief. 2020;(390):1-8.
  3. Lembke A, Humphreys K, Newmark J. Weighing the risks and benefits of chronic opioid therapy. Am Fam Physician. 2016;93(12):982-990.
  4. Flatters SJ. The contribution of mitochondria to sensory processing and pain. Prog Mol Biol Transl Sci. 2015;131:119-146. doi:1016/bs.pmbts.2014.12.004
  5. Sui BD, Xu TQ, Liu JW, et al. Understanding the role of mitochondria in the pathogenesis of chronic pain. Postgrad Med J. 2013;89(1058):709-714. doi:1136/postgradmedj-2012-131068
  6. Doyle TM, Salvemini D. Mini-review: mitochondrial dysfunction and chemotherapy-induced neuropathic pain. Neurosci Lett. 2021;760:136087. doi:1016/j.neulet.2021.136087
  7. Shen CL, Castro L, Fang CY, et al. Bioactive compounds for neuropathic pain: an update on preclinical studies and future perspectives. J Nutr Biochem. 2022;104:108979. doi:1016/j.jnutbio.2022.108979
  8. Yousuf MS, Maguire AD, Simmen T, Kerr BJ. Endoplasmic reticulum-mitochondria interplay in chronic pain: the calcium connection. Mol Pain. 2020;16:1744806920946889. doi:1177/1744806920946889
  9. Ilari S, Giancotti LA, Lauro F, et al. Natural antioxidant control of neuropathic pain—exploring the role of mitochondrial SIRT3 pathway. Antioxidants (Basel). 2020;9(11):1103. doi:3390/antiox9111103
  10.  Dai CQ, Guo Y, Chu XY. Neuropathic pain: the dysfunction of Drp1, mitochondria, and ROS homeostasis. Neurotox Res. 2020;38(3):553-563. doi:1007/s12640-020-00257-2
  11.  Lettieri-Barbato D, Cannata SM, Casagrande V, Ciriolo MR, Aquilano K. Time-controlled fasting prevents aging-like mitochondrial changes induced by persistent dietary fat overload in skeletal muscle. PLoS One. 2018;13(5):e0195912. doi:1371/journal.pone.0195912
  12.  Madkour MI, El-Serafi AT, Jahrami HA, et al. Ramadan diurnal intermittent fasting modulates SOD2, TFAM, Nrf2, and sirtuins (SIRT1, SIRT3) gene expressions in subjects with overweight and obesity. Diabetes Res Clin Pract. 2019;155:107801. doi:1016/j.diabres.2019.107801
  13.  Memme JM, Erlich AT, Phukan G, Hood DA. Exercise and mitochondrial health. J Physiol. 2021;599(3):803-817. doi:1113/JP278853
  14.  Brain K, Burrows TL, Rollo ME, et al. A systematic review and meta-analysis of nutrition interventions for chronic noncancer pain. J Hum Nutr Diet. 2019;32(2):198-225. doi:1111/jhn.12601
  15.  Dragan S, Serban MC, Damian G, Buleu F, Valcovici M, Christodorescu R. Dietary patterns and interventions to alleviate chronic pain. Nutrients. 2020;12(9):2510. doi:3390/nu12092510
  16.  Aleksandrova K, Koelman L, Rodrigues CE. Dietary patterns and biomarkers of oxidative stress and inflammation: a systematic review of observational and intervention studies. Redox Biol. 2021;42:101869. doi:1016/j.redox.2021.101869
  17.  Ronchetti S, Migliorati G, Delfino DV. Association of inflammatory mediators with pain perception. Biomed Pharmacother. 2017;96:1445-1452. doi:1016/j.biopha.2017.12.001
  18.  Wood RA. Diagnostic elimination diets and oral food provocation. Chem Immunol Allergy. 2015;101:87-95. doi:1159/000371680
  19.  Dupont C. Diagnosis of cow’s milk allergy in children: determining the gold standard? Expert Rev Clin Immunol. 2014;10(2):257-267. doi:1586/1744666X.2014.874946
  20.  Ballmer-Weber BK. Value of allergy tests for the diagnosis of food allergy. Dig Dis. 2014;32(1-2):84-88. doi:1159/000357077
  21.  Totsch SK, Waite ME, Sorge RE. Dietary influence on pain via the immune system. Prog Mol Biol Transl Sci. 2015;131:435-469. doi:1016/bs.pmbts.2014.11.013
  22.  Bäcklund R, Drake I, Bergström U, Compagno M, Sonestedt E, Turesson C. Diet and the risk of rheumatoid arthritis – a systematic literature review. Semin Arthritis Rheum. 2023;58:152118. doi:1016/j.semarthrit.2022.152118
  23.  Zeng J, Franklin DK, Das A, Hirani V. The effects of dietary patterns and food groups on symptomatic osteoarthritis: a systematic review. Nutr Diet. 2023;80(1):21-43. doi:1111/1747-0080.12781
  24.  Towery P, Guffey JS, Doerflein C, Stroup K, Saucedo S, Taylor J. Chronic musculoskeletal pain and function improve with a plant-based diet. Complement Ther Med. 2018;40:64-69. doi:1016/j.ctim.2018.08.001
  25.  Dzik KP, Skrobot W, Kaczor KB, et al. Vitamin D deficiency is associated with muscle atrophy and reduced mitochondrial function in patients with chronic low back pain. Oxid Med Cell Longev. 2019;2019:6835341. doi:1155/2019/6835341
  26.  Friedlander JI, Shorter B, Moldwin RM. Diet and its role in interstitial cystitis/bladder pain syndrome (IC/BPS) and comorbid conditions. BJU Int. 2012;109(11):1584-1591. doi:1111/j.1464-410X.2011.10860.x
  27.  Oh-Oka H. Clinical efficacy of 1-year intensive systematic dietary manipulation as complementary and alternative medicine therapies on female patients with interstitial cystitis/bladder pain syndrome. Urology. 2017;106:50-54. doi:1016/j.urology.2017.02.053
  28.  Huffman MM, Slack A, Hoke M. Bladder pain syndrome. Prim Care. 2019;46(2):213-221. doi:1016/j.pop.2019.02.002
  29.  Martínez-Lara A, Moreno-Fernández AM, Jiménez-Guerrero M, et al. Mitochondrial imbalance as a new approach to the study of fibromyalgia. Open Access Rheumatol. 2020;12:175-185. doi:2147/OARRR.S257470
  30.  Nadal-Nicolás Y, Miralles-Amorós L, Martínez-Olcina M, Sánchez-Ortega M, Mora J, Martínez-Rodríguez A. Vegetarian and vegan diet in fibromyalgia: a systematic review. Int J Environ Res Public Health. 2021;18(9):4955. doi:3390/ijerph18094955
  31.  Isasi C, Colmenero I, Casco F, et al. Fibromyalgia and non-celiac gluten sensitivity: a description with remission of fibromyalgia. Rheumatol Int. 2014;34(11):1607-1612. doi:1007/s00296-014-2990-6
  32.  Nijs J, Malfliet A, Ickmans K, Baert I, Meeus M. Treatment of central sensitization in patients with ‘unexplained’ chronic pain: an update. Expert Opin Pharmacother. 2014;15(12):1671-1683. doi:1517/14656566.2014.925446

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