Co-administration of Phycocyanobilin and/or Phase 2-Inducer Nutraceuticals for Prevention of Opiate Tolerance

Chronic use of opiates for control of chronic pain is complicated by the development of tolerance and hyperalgesia, and hence usually entails dose escalation and diminished efficacy. Our evolving understanding of the mechanisms mediating induction of morphine tolerance may enable discovery of adjunct measures which can prevent this tolerance; this essay proposes that certain nutraceuticals may have utility in this regard. Considerable evidence now points to an obligate role for production of peroxynitrite and other oxidants in the dorsal horn in development of morphine tolerance. Various isoforms of NADPH oxidase are the chief source of the superoxide which gives rise to these oxidants. Since heme oxygenase, via its products bilirubin and carbon monoxide, functions as a physiological inhibitor of various isoforms of NADPH oxidase, phase 2-inducing nutraceuticals with blood brain-barrier permeability such as lipoic acid, an effective inducer of heme oxygenase-1, may have potential for prevention of morphine tolerance; indeed, this has been demonstrated in a mouse study. The phycocyanobilin (PhyCB) chromophore of spirulina, a structural analog of biliverdin, shares bilirubin's ability to inhibit NAPDH oxidase complexes; hence, administration of spirulina or of PhyCB-enriched spirulina extracts merits evaluation in rodent models of morphine tolerance. Uric acid quenches peroxynitrite-derived radicals, and its plasma level can be boosting via supplementation with inosine; indeed, administration of inosine has been shown to counteract development of hyperalgesia in rodents. If practical doses of these agents can be shown to prevent morphine tolerance and hyperalgesia in rodents, their use as adjuvants to clinical opiate therapy should be assessed.