- 1 What is Naltrexone?
- 2 What is Ultra Low Dose Naltrexone?
- 3 How Does Ultra Low Dose Naltrexone Potentiate Opioids?
- 4 How Does ULDN Work to Reverse Opiate tolerance or tolerances of Other Drugs?
- 5 Why Ultra Low Dose Naltrexone, rather than Low Dose or even just Naltrexone?
- 6 What’s the Dosage and How Should It Be Taken?
- 7 What’s the Upper Ceiling?
- 8 Potential Interactions and Risks to Watch Out
- 9 Bonus Information
- 10 Research References
- 11 Related Posts
What is Naltrexone?
Naltrexone is described as a substituted oxymorphone, it’s active metabolites are antagonists at the u-opioid receptor (MOR), k-opioid receptor (KOR), and the o-opioid receptor (DOR).
Naltrexone’s primary use (in normal doses) is in the management of opioid and alcohol dependency. It is also often used to reduce Benzodiazepine withdrawal symptoms as both Benzodiazepines and alcohol rely on agonizing GABA receptors, which is also why addiction to alcohol or benzodiazepines are also notoriously difficult to treat.
Naltrexone reversibly blocks the effects of opiates to manage opiate dependency and also modulates the dopaminergic mesolimbic pathway – the reward center in the brain, together these reduce the feel good factor in the drugs and thus in theory allowing a reduction.
Obviously this doesn’t work very well…because simply put it also cancels a portion of the Opiates primary effects.
The interesting part about Naltrexone is when it is diluted into micrograms it changes into a totally different drug.
What is Ultra Low Dose Naltrexone?
Ultra Low Dose Naltrexone is an extremely diluted liquid solution of the drug Naltrexone.
It is even more diluted than the popular solution used for treating multiple sclerosis known as “Low Dose Naltrexone.
Note that Ultra Low Dose Naltrexone is NOT Low Dose Naltrexone.
Normal Naltrexone, ULDN (Ultra Low Dose Naltrexone) and LDN (Low Dose Naltrexone) all have different effects due to the differing effects on the Opiate receptors depending on dosage.
This will be covered in detail further on.
How Does Ultra Low Dose Naltrexone Potentiate Opioids?
Yes, studies show that ultra low dose Naltrexone show improvement in analgesic efficacy and an increased duration of analgesia, alleviation of tolerance and reversal.
6 Papers publish by Crain and Shen from 1990 to 2000 show reliably ULDN enhanced the level of analgesia as well as the duration from morphine.
a novel drug that combines oxycodone with ultralow-dose naltrexone, an opioid antagonist. Ultralow-dose opioid antagonists have been demonstrated to enhance and prolong opiate analgesia and alleviate opioid tolerance and withdrawal in rodents. This 3-week, Phase II clinical trial assessed safety and analgesic efficacy of Oxytrex in patients with moderate to severe pain from osteoarthritis. Patients with a pain score or =5 received placebo, oxycodone 4 times a day (qid), Oxytrex qid, or Oxytrex twice a day (bid). All active treatment groups received the same total daily dose and dose escalation of oxycodone starting at 10 and ending at 40 mg/day. Importantly, the Oxytrex bid group received a lower daily dose of naltrexone than Oxytrex qid (0.002 vs 0.004 mg/day). Oxytrex bid produced a 39% reduction in pain intensity, which was significantly greater than that of placebo (P < .001), oxycodone qid (P = .006), and Oxytrex qid (P = .003). Oxytrex bid was also superior to placebo in quality of analgesia (P = .002), duration of pain control each day (P = .05), patients’ global assessments (P = .04), and the Western Ontario and MacMaster Universities Osteoarthritis Index total score (P = .03). The incidence of side effects was comparable between active treatments. In this Phase II dose-ranging study, Oxytrex bid demonstrated greater pain relief with a more convenient dosing schedule compared to oxycodone qid.
J Pain. 2005 Jun;6(6):392-9.
Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of Oxytrex.
Chindalore VL1, Craven RA, Yu KP, Butera PG, Burns LH, Friedmann N.
Anniston Medical Clinic, Anniston, Alabama, USA.
For those who don’t know – Tolerance happens because as a person takes the same chemical many times, the body adapts and down-regulates the receptors to reduce the effect of the drug.
In addition ultra, low dose Naltrexone also prevents the development of drug tolerance to Opiates.
Recent preclinical and clinical studies have demonstrated that cotreatments with extremely low doses of opioid receptor antagonists can markedly enhance the efficacy and specificity of morphine and related opioid analgesics. Our correlative studies of the cotreatment of nociceptive types of dorsal-root ganglion neurons in vitro and mice in vivo with morphine plus specific opioid receptor antagonists have shown that antagonism of Gs-coupled excitatory opioid receptor functions by cotreatment with ultra-low doses of clinically available opioid antagonists, e.g. naloxone and naltrexone, markedly enhances morphine’s antinociceptive potency and simultaneously attenuates opioid tolerance and dependence.
These preclinical studies in vitro and in vivo provide cellular mechanisms that can readily account for the unexpected enhancement of morphine’s analgesic potency in recent clinical studies of post-surgical pain patients cotreated with morphine plus low doses of naloxone or nalmefene. The striking consistency of these multidisciplinary studies on nociceptive neurons in culture, behavioral assays on mice and clinical trials on post-surgical pain patients indicates that clinical treatment of pain can, indeed, be significantly improved by administering morphine or other conventional opioid analgesics together with appropriately low doses of an excitatory opioid receptor antagonist.
Crain SM, Shen K-F (2000) Antagonists of excitatory opioid receptor functions enhance morphine’s analgesic potency and attenuate tolerance/dependence liability. Pain 84:121-131.
Note that physical drug tolerance is independent of receptor tolerance, but somehow Naltrexone also prevents physical withdrawals that cause pain, known as Hyperalgesia.
Allowing lower levels of Naloxone to be used, also reduced additive potentiation.
How Does ULDN Work to Reverse Opiate tolerance or tolerances of Other Drugs?
Naltrexone acts on the mu opioid receptor, using allometric scaling from research in rats 1mg per kg will work out to be 1 picograms per kg
Mice were able to stay on the same dosage by adding Naltrexone 3 days later, without the need to increase the drug as you would normally need to.
Ultra Low Dose Naltrexone is speculated to have high affinity for an unknown site and is not acting as a classical antagonists. Only 1% of the opioid receptors are occupied at ultra low dose.
Higher dosages may cause interference with the above mechanism by binding at the classical receptor site instead of the unknown site.
Whatever this mechanism it is, ULDN is shown by scientists to work by preventing a switch in the G protein coupling that has been shown to occur drug chronic opiate administration.
The current standing theory is that ULDN acts to block receptor coupling tp G proteins
Opiates produce analgesia by activating mu opioid receptor-linked inhibitory G protein signaling cascades and related ion channel interactions that suppress cellular activities by hyperpolarization. After chronic opiate exposure, an excitatory effect emerges contributing to analgesic tolerance and opioid-induced hyperalgesia. Ultra-low-dose opioid antagonist co-treatment blocks the excitatory effects of opiates in vitro, as well as opioid analgesic tolerance and dependence, as was demonstrated here with ultra-low-dose naloxone combined with morphine. While the molecular mechanism for the excitatory effects of opiates is unclear, a switch in the G protein coupling profile of the mu opioid receptor and adenylyl cyclase activation by Gbetagamma have both been suggested. Using CNS regions from rats chronically treated with vehicle, morphine, morphine+ultra-low-dose naloxone or ultra-low-dose naloxone alone, we examined whether altered mu opioid receptor coupling to G proteins or adenylyl cyclase activation by Gbetagamma occurs after chronic opioid treatment. In morphine-naïve rats, mu opioid receptors coupled to Go in striatum and to both Gi and Go in periaqueductal gray and spinal cord. Although chronic morphine decreased Gi/o coupling by mu opioid receptors, a pronounced coupling to Gs emerged coincident with a Gbetagamma interaction with adenylyl cyclase types II and IV. Co-treatment with ultra-low-dose naloxone attenuated both the chronic morphine-induced Gs coupling and the Gbetagamma signaling to adenylyl cyclase, while increasing Gi/o coupling toward or beyond vehicle control levels. These findings provide a molecular mechanism underpinning opioid tolerance and dependence and their attenuation by ultra-low-dose opioid antagonists.
Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor-G protein coupling and Gbetagamma signaling.
Wang HY1, Friedman E, Olmstead MC, Burns LH.
1Department of Physiology and Pharmacology, City University of New York Medical School, 138th Street and Convent Avenue, New York, NY 10031, USA. firstname.lastname@example.org
Why Ultra Low Dose Naltrexone, rather than Low Dose or even just Naltrexone?
First of all, pure Naltrexone is a scary undesirable experience. Naltrexone is an opioid antagonist that means it’s pretty much the opposite of pain relief, misdoing can yield some extremely uncomfortable experiences.
Ultra Low Dose Naltrexone acts in a very different way than Low Dose Naltrexone. The referenced research shows ULDN is also capable of reversing tolerance on multiple papers referenced at the end of this article.
What’s the Dosage and How Should It Be Taken?
The studies shows that less is better, having more than (20micrograms) blocks the effects of opiates and removes the anti-tolerance effect.
The greatest level of tolerance reversal and reduction came from the lowest levels of Naltrexone!
This is an important point, anecdotally people are trying up from 1 microgram to 20 micrograms.
The suggested regiment from the research is 3 times a day, taken with the opiate together.
In the studies using allometric scaling only 1 to 2 micrograms would be used, if translated to human levels – however allometric scaling is not always accurate given the differences between
Extensive preclinical data have shown ultra-low-dose opioid antagonists to enhance and prolong the analgesic efficacy of opiates and prevent opioid tolerance (Crain and Shen, 1995; Powell et al., 2002; Shen et al., 2002a, b). The enhancement of analgesia is both an increase in potency and an increase in efficacy of the opiate. For example, in the mouse hot water tailflick assay, the antinociceptive effect of the EC50 dose of oxycodone (1 mg/kg, s.c.) was enhanced by the addition of 1 pg/kg naltrexone, while the antinociceptive effect of an EC100 dose of oxycodone (3 mg/kg, s.c.) was also enhanced by ultra-low-dose naltrexone, here at 3 pg/kg (Fig. 1). In addition, the duration of action is prolonged.
Recent Developments in Pain Research, 2005: 115-136 ISBN: 81-308-0012-8 Editor: Anna Capasso
Ultra-low-dose opioid antagonists enhance opioid analgesia while reducing tolerance, dependence and addictive properties
Lindsay H. Burns
Pain Therapeutics, Inc., South San Francisco, CA, USA
What’s the Upper Ceiling?
20 micrograms appears to be the upper limit.
It is highly likely that trying anything 1 to 10 micrograms is feasible. Allometric scaling is notoriously unreliable.
Potential Interactions and Risks to Watch Out
At such low doses Naltrexone should have next to no side effects, in fact it should reduce the side effect profile of Opiates (when tolerance has developed and higher dosages are in play).
Normal Naltrexone can be overdosed at levels beyond 1500mg, it is a common mistake to think Naltrexone cancels out the dangerous fatal depressive effects of opiates like Morphine or Heroin. It does not, it is entirely common for people to overdose on Opiates because they think Naltrexone will block the effects of the Opiates completely.
A Naltrexone overdose can cause liver damage, cause pain and extreme fatigue and even become fatal. On normal doses it can cause stomach cramps, diarrhoea, headaches, and muscle aches and more.
Mice Deficient in B-Arrestin-2 pkcy or the delta opioid receptor do not develop opioid tolerance. Naltrexone happens to target delta opioid receptors.
Low Dose Naltrexone (A little higher dosage than ULDN but still much lower than tablet form) is a very popular liquid solution for a whole bunch of other ailments such as Multiple Sclerosis.
Disclaimer: All thoughts and advice expressed are the personal opinions and gatherings of the author and do not constitute medical advice. If you are seeking medical advice please consult a doctor.
Arner S, Rawal N, Gustafsson LL (1988) Clinical experience of long-term treatment with eppidural and intrathecal opioids — a nationwide survey. Acta Anaesthesiol Scand 32:253- 259.
2. American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition, Text Revised (DSM-IV). Washington, D.C.
3. Avidor-Reiss T, Bayewitch M, Levy R, Matus-Leibovitch N, Nevo I, Vogel Z (1995) Adenylyl cyclase supersensitization in mu-opioid receptor-transfected Chinese hamster ovary cells following chronic opioid treatment. J Biol Chem 270:29732-29738.
4. Ballantyne J, Mao J (2003) Opioid therapy for chronic pain. N Engl J Med 349:1943-1953.
5. Bardo M, Bevins R (2000) Conditioned place preference: what does it add to our preclinical
understanding of drug reward? Psychopharmacology 153:31-43.
6. Bechara A, Nader K, van der Kooy D (1995) Neurobiology of withdrawal motivation:
evidence for two separate aversive effects produced in morphine-naive versus morphine-
dependent rats by both naloxone and spontaneous withdrawal. Behav Neurosci 109:91-105.
7. Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG (2000) Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature
8. Breivogel C, Selley DE, Childers SR (1997) Acute and chronic effects of opioids on delta and
mu receptor activation of G-proteins in NG108-15 an SK-N-SH cell membranes. J
9. Cepeda MS, Alvarez H, Morales O, Carr DB (2004) Addition of ultralow dose naloxone to
postoperative morphine PCA: unchanged analgesia and opioid requirement but decreased incidence of opioid side effects. Pain 107:41-46.
134 Lindsay H. Burns
10. Cepeda MS, Africano JM, Manrique AM, Fragoso W, Carr DB (2002) The combination of low dose naloxone and morphine in PCA does not decrease opioid requirements in the postoperative period. Pain 96:73-79.
11. Chindalore VL, Butera PG, Yu KP, Burns LH, Friedmann N (2005) Adding Ultralow-Dose Naltrexone to Oxycodone Enhances and Prolongs Analgesia: A Randomized, Controlled Trial of Oxytrex. J Pain 6:392-399.
12. Cicero T, Aylward S, Meyer E (2003) Gender differences in the intravenous self- administration of mu opiate agonists. Pharmacol Biochem Behav 74:541-549.
13. Collins R, Weeks J, Cooper M, Good P, Russell R (1984) Prediction of abuse liability of drugs using IV self-administration by rats. Psychopharmacology 82:6-13.
14. Connor M, Christie MD (1999) Opioid receptor signalling mechanisms. Clin Exp Pharmacol Physiol 26:493-499.
15. Crain SM, Shen K-F (1990) Opioids can evoke direct receptor-mediated excitatory effects on sensory neurons. Trends Pharmacol Sci 11:77-81.
16. Crain SM, Shen K-F (1992a) After chronic opioid exposure sensory neurons become supersensitive to the excitatory effects of opioid agonists and antagonists as occurs after acute elevation of GM1 ganglioside. Brain Research 575:13-24.
17. Crain SM, Shen K-F (1992b) After GM1 ganglioside treatment of sensory neurons naloxone paradoxically prolongs the action potential but still antagonizes opioid inhibition. JPET 260:182-186.
18. Crain SM, Shen K-F (1995) Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment. Proc Natl Acad Sci USA 92:10540-10544.
19. Crain SM, Shen K-F (2001) Acute thermal hyperalgesia elicited by low-dose morphine in normal mice is blocked by ultra-low-dose naltrexone, unmasking potent opioid analgesia. Brain Research 888:75-82.
20. Cruciani RA, Lussier D, Miller-Saultz D, Arbuck DM (2003) Ultra-low dose oral naltrexone decreases side effects and potentiates the effect of methadone. J Pain Symptom Management 25:491-494.
21. Crain SM, Shen K-F (2000) Antagonists of excitatory opioid receptor functions enhance morphine’s analgesic potency and attenuate tolerance/dependence liability. Pain 84:121-131.
22. Evans C (2004) Secrets of the opium poppy revealed. Neuropharmacology 47:Suppl 1:293- 299.
23. Fine P (2004) Opioid insights: opioid-induced hyperalgesia and opioid rotation. J Pain Palliat Care Pharmacother 18:75-79.
24. Gan TJ, Ginsberg B, Glass PSA, Fortney J, Jhaveri R, Perno R (1997) Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate. Anesthesiology 87:1075-1081.
25. Gintzler AR, Chakrabarti S (2001) Opioid tolerance and the emergence of new opioid receptor-coupled signaling. Molecular Neurobiology 21:21-33.
26. Heit H (2003) Addiction, physical dependence, and tolerance: precise definitions to help clinicians evaluate and treat chronic pain patients. J Pain Palliat Care Pharmacother 17:15-29.
27. Joranson D, Ryan K, Gilson A, Dahl J (2000) Trends in medical use and abuse of opioid
analgesics. J Am Med Assoc 283:1710-1714.
28. Joshi GP, Duffy L, Chehade J, Wesevich J, Gajraj N, Johnson ER (1999) Effects of
prophylactic nalmefene on the incidence of morphine-related side effects in patients receiving
intravenous patient-controlled analgesia. Anesthesiology 90:1007-1011.
29. Kayser V, Besson JM, Guilbaud G (1987) Paradoxical hyperalgisic effect of exceedingly low doses of systemic morphine in an animal model of persistent pain (Freund’s adjuvant-induced
￼arthritis rats). Brain Res 414:155-157.
Ultra-low-dose opioid antagonists improve opioid therapy
￼30. Kiyatkin EA (1989) Morphine: some puzzles of a well-known substance. Int J Neurosci 45:231-246.
31. Kogan MJ, Verebey K, Mule SJ (1977) Estimation of the systemic availability and other pharmacokinetic parameters of naltrexone in man after acute and chronic oral administration. Res Commun Chem Pathol Pharmacol 18:29-34.
32. Koob G (1992) Neural mechanisms of drug reinforcement. Ann N Y Acad Sci 654:171-191.
33. Koob GF, Stinus L, Le Moal M, Bloom FE (1989) Opponenet process theory of motivation:
neurobiological evidence from studies of opiate dependence. Neurosci Biobehav Rev 13:135-140.
34. Laugwitz KL, Offermanns S, Spicher K, Schultz G (1993) Mu and delta opioid receptors differentially couple to G protein subtypes in membranes of human neuroblastoma SH-SY5Y
cells. Neuron 10:233-242.
35. Leow K, Smith M, Williams B, Cramond T (1992) Single-dose and steady-state
pharmacokinetics and pharmacodynamics of oxycodone in patients with cancer. Clin
Pharmacol Ther 52:487-495.
36. Leri F, Burns LH (2005) Ultra-low-dose naltrexone reduces rewarding potency of oxycodone
and relapse vulnerability in rats. Pharmacology, Biochemistry and Behavior, in press.
37. Li X, Angst M, Clark J (2001) Opioid-induced hyperalgesia and incisional pain. Anesth
38. Matsumoto A, Ma T, Babul N, Ahdieh H, Lee D (2002) Oxymorphine ER (20 mg and 40 mg)
provides superior efficacy compared with placebo and oxycontin (20 mg) in pain associated with osteoarthritis: results of a randomized, controlled trial. In: 10th World Congress of Pain. San Diego, CA.
39. Miser A, Chayt K, Sandlund J, Cohen P, Dothage J, Miser J (1986) Narcotic withdrawal syndrome in young adults after the therapeutic use of opiates. Am J Dis Child 140:603- 604.
40. Nitsche JF, Schuller AGP, King MA, Zengh M, Pasternak GW (2002) Genetic dissociation of opiate tolerance and physical dependence in delta-opioid receptor-1 and preproenkephalin knock-out mice. J Neurosci 22:10906-10913.
41. Olmstead MC, Burns LH (2005) Ultra-low-dose naltrexone suppresses rewarding effects of opiates and aversive effects of opiate withdrawal in rats. Psychopharmacology, in press.
42. Oxbro K, Trang T, Sutak M, Jhamandas KH (2003) The effects of spinal ultra-low doses of an opioid receptor antagonist on systemic morphine dependence. In: Society for Neuroscience.
43. Powell KJ, Abul-Husn NS, Jhamandas A, Olmstead MC, Beninger RJ, Jhamandas K (2002) Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats. JPET 300:588-596.
44. Poyhia R, Vainio A, Kalso E (1993) A review of oxycodone’s clinical pharmacokinetics and pharmacodynamics. J Pain Symptom Manage 8:63-67.
45. Poyhia R, Seppala T, Olkkola K, Kalso E (1992) The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects. Br J Clin Pharmacol 33:617-621.
46. Roth SH, Fleischmann RM, Burch FX, Dietz R, Bockow B, Rapoport RJ, Rutstein J, Lacouture PG (2000) Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain. Arch Intern Med 160:853-860.
47. Shaham Y, Shalev U, Lu L, de Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168:3-20.
48. Shen KF, Crain SM (1989) Dual opioid modulation of the action potential duration of mouse dorsal root ganglion neurons in culture. Brain Research 491:227-242.
49. Shen KF, Crain SM (1994) Antagonists at excitatory opioid receptors on sensory neurons in culture increase potency and specificity of opiate analgesics and attenuate development of tolerance/dependence. Brain Res 636:286-297.