Chronic low back pain (cLBP) is the most prevalent chronic pain condition. There are no treatments that haven been found to directly assuage evoked cLBP. To this extent, mindfulness-meditation is a promising pain therapy. Yet, it is unclear if meditation can be utilized to directly attenuate evoked chronic pain through endogenous opioids. A double-blind, randomized, and placebo-controlled clinical trial with a drug crossover design examined if mindfulness-meditation, as compared to sham mindfulness-meditation, attenuated straight leg-raise test evoked chronic pain during intravenous (0.15 mg/kg bolus + 0.15 mg/kg/hour maintenance) naloxone (opioid antagonist) and placebo-saline infusion. Fifty-nine individuals with cLBP (mean age = 46 years; 30 females) completed all study procedures. After the pre-intervention pain testing session, patients were randomized to a four-session (20-min/session) mindfulness (n = 30) or sham mindfulness-meditation (n = 29) intervention. After the interventions, mindfulness and sham mindfulness-meditation were associated with significant reductions in back pain during saline and naloxone infusion when compared to rest (non-meditation) in response to the cLBP-evoking straight leg-raise test. These results indicate that meditation directly reduces evoked chronic pain through non-opioidergic processes. Importantly, after the interventions, the mindfulness group reported significantly lower straight leg-raise induced pain than the sham mindfulness-meditation group during rest (non-meditation) and meditation. Mindfulness and sham mindfulness-meditation training was also associated with significantly lower Brief Pain Inventory severity and interference scores. The pain-relieving effects of mindfulness meditation were more pronounced than a robust sham-mindfulness meditation intervention, suggesting that non-reactive appraisal processes may be uniquely associated with improvements in chronic low-back pain.Trial Registration: ClinicalTrials.gov identifier: NCT04034004.

Converging lines of preclinical and clinical research indicate that females, in stark contrast to males, display an increased prevalence of chronic pain. Females also demonstrate weaker analgesic efficacy in response to opioid therapies when compared with males. These sex-specific differences may be driven by dimorphic endogenous opioidergic responses. In rodent models, analgesia exhibited in males but not females was reversed by inhibiting endogenous opioidergic reception. In humans, the sex-specific endogenous system(s) supporting the direct attenuation of evoked pain has not been identified. To determine whether opioidergic blockade reverses self-regulated analgesia in males as compared to females, the present study combined two operationally analogous clinical trials (n = 98; 51 females and 47 males). In a double-blinded, counterbalanced study involving healthy (n = 39) and chronic low back pain (n = 59) populations, a high-dose naloxone (μ-, κ-, δ-opioid antagonist) vs. placebo-saline cross-over design (15 mg/kg bolus +0.1 mg/kg/h) tested the hypothesis that endogenous opioids mediate analgesia in males but not females. An 11-point visual analog scale (VAS) (0 = no pain; 10 = worst pain imaginable) evaluated pain ratings in response to noxious heat stimulation (49 °C; calf). After baseline pain testing, participants were randomized to a validated four-session mindfulness meditation or sham mindfulness meditation training intervention. Participants practiced their respective meditation during noxious heat, intravenous high-dose naloxone, and placebo saline, respectively. In males and females, meditation significantly lowered evoked pain during saline infusion. Intravenous naloxone inhibited analgesia in males, but pain relief was well preserved in females. The present findings indicate that endogenous opioids mediate self-regulated analgesia in males but not females and underscore the need to establish sex-specific pain therapeutics.