Minocycline does not affect experimental pain or addiction-related outcomes in opioid maintained patients
Minocycline, a tetracycline antibiotic, inhibits activation of microglia. In preclinical studies, minocycline prevented development of opioid tolerance and opioid-induced hyperalgesia (OIH). The goal of this study was to determine if minocycline changes pain threshold and tolerance in individuals with opioid use disorder who are maintained on agonist treatment.
In this double-blind, randomized human laboratory study, 20 participants were randomized to either minocycline (200 mg/day) or placebo treatment for 15 days. The study had three test sessions (days 1, 8, and 15 of treatment) and one follow-up visit 1 week after the end of treatment. In each test session, participants were assessed on several subjective and cognitive measures, followed by assessment of pain sensitivity using the Cold Pressor Test (CPT). Daily surveys and cognitive measures using Ecological Momentary Assessment (EMA) were also collected four times a day on days 8 through 14 of treatment, and proinflammatory serum cytokines were assessed before and on the last day of treatment.
Minocycline treatment did not change pain threshold or tolerance on the CPT. Similarly, minocycline did not change severity of pain, opioid craving, withdrawal, or serum cytokines. Minocycline treatment increased accuracy on a Go/No-Go task.
While these findings do not support minocycline’s effects on OIH, minocycline may have a potential use as a cognitive enhancer for individuals with opioid use disorder, a finding that warrants further systematic studies.
KeywordsOpioid Hyperalgesia EMA Microglia Minocycline
This study was conducted during Dr. Arout’s postdoctoral fellowship at Yale University School of Medicine (NIDA T32 DA007238; Principal Investigator: I. L. Petrakis) and was supported by the VA New England Mental Illness Research, Education and Clinical Center (MIRECC). We would like to thank Dr. Lesley Devine of Yale University School of Medicine for executing the serum cytokine analysis.
Compliance with ethical standards
Conflicts of interest
The authors declare that there is no conflict of interest.
- Akgűn E, Lunzer MM, Portoghese P (2018) Combined glia inhibition and opioid receptor agonism afford highly potent analgesics without tolerance ACS chemical neuroscienceGoogle Scholar
- Chapman CR, Lipschitz DL, Angst MS, Chou R, Denisco RC, Donaldson GW, Fine PG, Foley KM, Gallagher RM, Gilson AM, Haddox JD, Horn SD, Inturrisi CE, Jick SS, Lipman AG, Loeser JD, Noble M, Porter L, Rowbotham MC, Schoelles KM, Turk DC, Volinn E, von Korff MR, Webster LR, Weisner CM (2010) Opioid pharmacotherapy for chronic non-cancer pain in the United States: a research guideline for developing an evidence-base. J Pain 11:807–829CrossRefGoogle Scholar
- Cui Y, Liao XX, Liu W, Guo RX, Wu ZZ, Zhao CM, Chen PX, Feng JQ (2008) A novel role of minocycline: attenuating morphine antinociceptive tolerance by inhibition of p38 MAPK in the activated spinal microglia. Brain Behav Immun 22:114–123. https://doi.org/10.1016/j.bbi.2007.07.014 CrossRefPubMedGoogle Scholar
- Curtin CM, Kenney D, Suarez P, Hentz VR, Hernandez-Boussard T, Mackey S, Carroll IR (2017) A double-blind placebo randomized controlled trial of minocycline to reduce pain after carpal tunnel and trigger finger release. J Hand Surg 42:166–174. https://doi.org/10.1016/j.jhsa.2016.12.011 CrossRefGoogle Scholar
- Hutchinson MR, Northcutt AL, Chao LW, Kearney JJ, Zhang Y, Berkelhammer DL, Loram LC, Rozeske RR, Bland ST, Maier SF, Gleeson TT, Watkins LR (2008) Minocycline suppresses morphine-induced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced analgesia. Brain Behav Immun 22:1248–1256CrossRefGoogle Scholar
- McNair D, Lorr M, Droppleman L (1992) POMS Manual–Profile of Mood Questionnaire San Diego: EditsGoogle Scholar
- Rezapour T, DeVito EE, Sofuoglu M, Ekhtiari H (2016) Perspectives on neurocognitive rehabilitation as an adjunct treatment for addictive disorders: from cognitive improvement to relapse prevention. In: Progress in brain research, vol 224. Elsevier, pp 345–369Google Scholar
- Ricardo Buenaventura M, Rajive Adlaka M, Nalini Sehgal M (2008) Opioid complications and side effects. Pain Phys 11:S105–S120Google Scholar
- Samour MS, Nagi SS, Shortland PJ, Mahns DA (2017) Minocycline prevents muscular pain hypersensitivity and cutaneous allodynia produced by repeated intramuscular injections of hypertonic saline in healthy human participants. J Pain 18:994–1005. https://doi.org/10.1016/j.jpain.2017.03.009 CrossRefPubMedGoogle Scholar
- Stone AA, Shiffman S (1994) Ecological momentary assessment (EMA) in behavorial medicine Annals of Behavioral MedicineGoogle Scholar
- Vanelderen P, van Zundert J, Kozicz T, Puylaert M, de Vooght P, Mestrum R, Heylen R, Roubos E, Vissers K (2015) Effect of minocycline on lumbar radicular neuropathic pain: a randomized, placebo-controlled, double-blind clinical trial with amitriptyline as a comparator. Anesthesiology 122:399–406. https://doi.org/10.1097/aln.0000000000000508 CrossRefPubMedGoogle Scholar
- Zhang L, Zheng H, Wu R, Zhu F, Kosten TR, Zhang XY, Zhao J (2018) Minocycline adjunctive treatment to risperidone for negative symptoms in schizophrenia: association with pro-inflammatory cytokine levels. Prog Neuro-Psychopharmacol Biol Psychiatry 85:69–76. https://doi.org/10.1016/j.pnpbp.2018.04.004 CrossRefGoogle Scholar