The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 18 No. 6 • October 2015


RELIEF FROM INTRACTABLE PAIN BY ENHANCING THE EFFECTS OF OPIATES WITH NATURAL PRODUCTS

People who are having intolerable pain, such as those with far advanced cancer, have the problem both of getting opiates to treat their pain and of the fact that opiates have limits in their effectiveness in really severe pain. Here are a couple of suggestions for what can be done with simple easily available totally legal no prescription needed supplements that have been shown to enhance the effectiveness of morphine.

CHOLINE ENHANCES THE EFFECT OF MORPHINE

Choline and acetylcholine agonists have been shown in animal studies to have antinociceptive (to decrease pain) effects. (Rowley, 2010) (Serrano, 1994) (Yong-Ping, 2011). As described in Rowley, 2010, choline provided (in mice) “moderately effective analgesic via activation of alpha7 nicotinic acetylcholine receptors.” Cholinesterase inhibitors (such as galantamine, which is active at the alpha7 nicotinic acetylcholine receptor) are known to have analgesic activity (Rowley, 2010) Importantly, the administration of choline (2 mg/kg) with morphine (0.165 mg/kg) significantly increased the pain-killing efficacy of morphine in the late phase but not in the early phase (Wang, 2005).

Moreover, the combination of cholinergic agonists and aspirin provided significantly enhanced relief of pain in a model where mice received painful acetic acid intraventricular injections. (Yong-Ping, 2011) The same effect would be expected with the combination of cholinergic agonists and other NSAIDS.

In addition, another report (Serrano, 1994) showed in rats and mice subjected to painful acetic acid and to the tail flick test (where the animal removes its tail from a hot plate when it gets painful), that the antipain effects of taurine required peripheral cholinergic mechanisms. In studies done before (Serrano, 1994), the authors note, taurine prevented the development of tolerance to a centrally administered enkephalin analog (enkephalin is an endogenous opioid).

There is some evidence that cholinergic agonists and TRPV1 (vanilloid) receptors have antinociceptive effects (Origoni, 2013), and the combination is synergistic. (ref vanished) The TRPV1 (vanilloid) receptor is sometimes called the capsaicin receptor because hot peppers containing capsaicin activate that receptor, manifested by sweating and skin flushing. It is also activated by vanillin, the major constituent of vanilla. Incidentally, you can get vanillin by buying “synthetic vanilla” at the supermarket; as the major constituent of vanilla, it tastes a lot like vanilla but has to be labeled as “synthetic vanilla.” It has recently been discovered that niacin activates the TRPV1 receptor, explaining at least in part the flush you get from hot peppers (Ma, 2014). This suggests (but we have not seen a test of this) that niacin might act to increase the antipain effects of TRPV1 agonists and combinations of cholinergic and TRPV1 agonists.

REDUCING PAIN BY INHIBITING TRPV1, THE CAPSAICIN RECEPTOR, WITH OTC DRUG

TRPV1 is a pain detecting receptor, but desensitizing it, by for example eating a lot of hot chili, is a way to reduce pain. It has been discovered that the TRPV1 receptor can be downregulated (desensitized) by mu opioid drugs. Mu opioid drugs includes morphine and fentanyl, but interestingly there is an OTC drug that activates the mu opioid receptor that will do the same thing to the TRPV1 receptor. We refer to loperamide, a PERIPHERAL mu opioid receptor agonist that does not pass the blood brain barrier and, hence, cannot cause addiction, respiratory depression, itching, and other side effects of central mu opiate activity. Loperamide is used to treat diarrhea, firming up feces, and unsurprisingly a side effect of taking too much is constipation. Use according to label instructions.

A paper (Butelman, 2004) reports that rhesus monkeys exposed to capsaicin to induce pain (assessed by a tail withdrawal assay), “loperamide (0.1-1 mg. /kg sc) acting as a peripherally selective mu-agonist after sc [subcutaneous] administration, produced a prevention of topical capsaicin-induced allodynia [pain induced stress].” However, loperamide did not prevent pain induced by heat, presumed to be a centrally mediated effect of mu agonist. Fentanyl, a mu agonist centrally active opioid, was more effective than loperamide at REVERSING pain induced by capsaicin and could PREVENT pain induced by both capsaicin and heat. Peripheral mu receptor agonists (such as loperamide) are reported to be particularly effective in decreasing pain due to inflammatory hypersensitivity (Endres-Becker, 2007)

  • Butelman, et al. Antiallodynic effects of loperamide and fentanyl against topical capsaicin-induced allodynia in unanesthetized primates. J Pharmacol Exp Ther. 311:155-63 (2004).
  • Endres-Becker, et al. Mu opioid receptor activation modulates transient receptor potential vanilloid 1 (TRPV1) currents in sensory neurons in a model of inflammatory pain. Mol Pharmacol. 71:12-8 (2007).
  • Kumar, Priyadarsini, et al. Inhibition of peroxynitrite-mediated reactions by vanillin. J Agric Food Chem. 52:139-45 (2004).
  • Origoni, Maggiore, et al. Neurobiological mechanisms of pelvic pain. Biomed Res Int. 2014:903848. doi: 10.1155/2014/903848. Epub 2014 Jul 8. (2014).
  • Ying-Pong et al. Pharmacological action of choline and aspirin coadministration on acute inflammatory pain. Eur J Pain. 15:858- 65 (2011).
  • Rowley, et al. Antinociceptive and anti-inflammatory effects of choline in a mouse model of postoperative pain. Br J Anaesth. 105(2):201-7 (2010).
  • Ma, Lee, Mao, et al. Nicotinic acid activates the capsaicin receptor TRPV1—a potential mechanism for cutaneous flushing. Arterioscler Thromb Vasc Biol. 14(6):1272-80 (2014).

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