Nature's First "Atypical Opioids": Kratom and Mitragynines.
Nature's First "Atypical Opioids": Kratom and Mitragynines.
Nature's First "Atypical Opioids": Kratom and Mitragynines.
DOI: 10.1111/jcpt.12676
C O M M E N TA RY
R. B. Raffa PhD1,2 | J. V. Pergolizzi Jr, MD3 | R. Taylor Jr, PhD3 |
M. H. Ossipov PhD4 | NEMA Research Group
1
University of Arizona College of Pharmacy,
Tucson, AZ, USA Summary
2
Temple University School of Pharmacy, What is known and objective: Advances in pain research have led to an understand-
Philadelphia, PA, USA
ing that many pains are driven by more than one underlying (patho)physiologic cause
3
NEMA Research, Inc., Naples, FL, USA
(ie, they are “multimechanistic”) and that better pain relief is obtained with fewer
4
Research Professor Emeritus, University
of Arizona College of Medicine, Tucson, AZ, adverse effects when an analgesic is correspondingly multimechanistic. At least two
USA of the more-modern analgesics combine opioid and non-opioid mechanisms, and
Correspondence have become known as “atypical opioids.” Less well known is that just as Nature
Robert B. Raffa, University of Arizona evolved opioids, it also evolved atypical opioids, presaging modern drug discovery
College of Pharmacy, Tucson, AZ, USA.
Email: robert.raffa@gmail.com efforts.
Comment: Traditional (typical) opioids are extracts or analogs of substances derived
from the poppy plant. They produce their analgesic and adverse effects primarily through
a single, opioid mechanism (albeit with individual differences). Two most recent analge-
sics were developed to have both an opioid mechanism and, a second, non-opioid mech-
anism of action (inhibition of monoamine neurotransmitter reuptake). Little known is
that Nature had already evolved a plant source of compounds with the same
properties.
What is new and conclusion: As debate about the use and abuse potential of kratom
swirls, conflicting, often contradicting, opinions are expressed. A review of the basic
pharmacology of kratom reveals the explanation for the bifurcation in viewpoints:
kratom has both opioid and non-opioid properties. Fascinatingly, just as the poppy
plant (Papaver) evolved the typical opioids, Mitragyna evolved the mitragynines—
Nature’s “atypical opioids.”
KEYWORDS
analgesic, kratom, neurotransmitter, non-opioid, opioid, pharmacognosy
1 | W H AT I S K N OW N A N D O B J EC TI V E for abuse intensifies, even regulatory agencies take what seems
like contradictory points of view regarding kratom’s effects, and
Technically, “kratom” is one of the common names for an ever- whether or not it should be scheduled as a controlled substance. 3
green tree in the coffee family (Mitragyna speciosa) that is native The confusion is magnified when attempts are made to classify
to South-E ast Asia.1 But, because of the use of its dried leaves kratom as either an opioid or a non-o pioid. A review of kratom’s
or extract(s) for an energy boost or various medicinal purposes, 2 chemistry and basic pharmacology reveals that it is actually
“kratom” has come to indicate the leaves or other parts of the both.4 More importantly, it reveals that Nature evolved a second
plant, or even to the active ingredients (Figure 1). As the debate plant source of opioids and, further, a natural source of “atypical
about kratom’s postulated therapeutic properties and potential opioids.”
J Clin Pharm Ther. 2018;1–5. © 2018 John Wiley & Sons Ltd | 1
wileyonlinelibrary.com/journal/jcpt
|
2 RAFFA et al
an equally important contribution from a non-o pioid mechanism and colleagues). Out of the more than twenty alkaloids present in
of action. kratom, the main active ingredients are the two indole alkaloids mi-
Buprenorphine and tramadol are examples of analgesics that tragynine (MG) and 7-
hydroxymitragynine (7-
OH-
MG) (Figure 2).
were found to have multiple mechanisms of analgesic action after The details of their pharmacology have been published and are thus
their synthesis. Buprenorphine has very high affinity for MOR, only summarized here:33-37
which is a major mechanism of its analgesic action.15 It has been
shown to have an additional supraspinal naloxone-, PTX (pertussis
2.4.1 | Opioid pharmacology
toxin)-, and NOP (nociception/orphanin FQ peptide)-insensitive, Gz-
and Ser-/ Thr-sensitive mechanism, and possibly other contributory
mechanisms.16 Tramadol produces its analgesic effect by the com- • MG and 7-OH-MG bind to opioid receptors with nM affinity
bined action of the enantiomers of parent drug and enantiomers of (MOR > DOR and KOR) and efficacy (agonist action).
its O-desmethyl (M1) metabolite. Tramadol has at least three mech- • MG and 7-OH-MG produce antinociceptive effect when adminis-
anisms: affinity for MOR, inhibition of neuronal norepinephrine re- tered orally, s.c., or directly into brain ventricles.
uptake (NRI), and inhibition of neuronal reuptake of serotonin (SRI). • The antinociceptive effect is antagonized by naloxone and the
Tapentadol was chemically engineered to possess strong analgesic more MOR-selective antagonist cyprodime (but less so by the
efficacy by combining specific dual mechanisms of analgesic action more DOR- and KOR-selective antagonists naltrindole and
(“directed polypharmacology”).17,18 The two mechanisms are acti- nor-binaltorphimine respectively).
vation of MOR and the inhibition of neuronal reuptake of norepi- • Antinociceptive tolerance develops with 7-OH-MG, as does
nephrine (MOR-NRI).19-24 This was accomplished by building on the cross-tolerance to morphine.
experience with the weaker analgesic tramadol, with the following • Naloxone precipitates withdrawal signs in 7-OH-MG-tolerant an-
major changes: minimize SRI activity; have both analgesic mecha- imals, but the withdrawal is milder than that from morphine.
nisms reside in a single molecule; and eliminate active metabolite(s).
The outcome is that tapentadol is more potent in a variety of animal
pain models, and in clinical trials has been shown to have compara-
ble efficacy to oxycodone, with more favourable tolerability. 25-31
Because of the distinction of these drugs, mechanistically and
clinically, from the typical opioids (meaning contributory opioid and
non-opioid mechanisms), they have become known as “atypical opi-
oids.” Interestingly, these compounds originated in drug discovery
laboratories. But unbeknownst to the discoverers of these drugs,
Nature had already evolved plants that contain natural substance
compounds that possess both opioid and non-opioid properties.
The plant source is Mitragyna (kratom), and the substances are the
mitragynines.4
R. B. Raffa http://orcid.org/0000-0002-1456-4451
The contribution of the dual components is evident in at least two
J. V. Pergolizzi http://orcid.org/0000-0001-5658-1471
pharmacologic characteristics:
R. Taylor http://orcid.org/0000-0001-5971-361X
19. Benade V, Nirogi R, Bhyrapuneni G, et al. Mechanistic evalua- 3 0. Hale M, Upmalis D, Okamoto A, Lange C, Rauschkolb C. Tolerability
tion of tapentadol in reducing the pain perception using in- of tapentadol immediate release in patients with lower back pain
vivo brain and spinal cord microdialysis in rats. Eur J Pharmacol. or osteoarthritis of the hip or knee over 90 days: a randomized,
2017;809:224‐230. double-blind study. Curr Med Res Opin. 2009;25:1095‐1104.
20. Tzschentke TM, Christoph T, Kogel B, et al. (-)-(1R,2R)-3-(3-dimethy 31. Daniels SE, Upmalis D, Okamoto A, Lange C, Haeussler J. A ran-
lamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol domized, double-blind, phase III study comparing multiple doses of
HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake tapentadol IR, oxycodone IR, and placebo for postoperative (bunio-
inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp nectomy) pain. Curr Med Res Opin. 2009;25:765‐776.
Ther. 2007;323:265‐276. 32. Jansen KL, Prast CJ. Ethnopharmacology of kratom and the
21. Tzschentke TM, de Vry J, Terlinden R, et al. Tapentadol hydrochlo- Mitragyna alkaloids. J Ethnopharmacol. 1988;23:115‐119.
ride: analgesic mu-opioid receptor agonist noradrenaline reuptake 33. Takayama H, Ishikawa H, Kurihara M, et al. Studies on the synthesis
inhibitor. Drugs Future. 2006;31:1053‐1061. and opioid agonistic activities of mitragynine-related indole alka-
22. Tzschentke TM, Jahnel U, Kogel B, et al. Tapentadol hydrochloride: loids: discovery of opioid agonists structurally different from other
a next-generation, centrally acting analgesic with two mechanisms opioid ligands. J Med Chem. 2002;45:1949‐1956.
of action in a single molecule. Drugs Today (Barc). 2009;45:483‐496. 3 4. Takayama H. Chemistry and pharmacology of analgesic indole alka-
23. Kress HG. Tapentadol and its two mechanisms of action: is there loids from the rubiaceous plant, Mitragyna speciosa. Chem Pharm
a new pharmacological class of centrally-acting analgesics on the Bull (Tokyo). 2004;52:916‐928.
horizon? Eur J Pain. 2010;14:781‐783. 35. Matsumoto K, Horie S, Ishikawa H, et al. Antinociceptive effect of
24. Schröder W, Vry JD, Tzschentke TM, Jahnel U, Christoph T. 7-hydroxymitragynine in mice: discovery of an orally active opioid
Differential contribution of opioid and noradrenergic mechanisms analgesic from the Thai medicinal herb Mitragyna speciosa. Life Sci.
of tapentadol in rat models of nociceptive and neuropathic pain. Eur 2004;74:2143‐2155.
J Pain. 2010;14:814‐821. 36. Matsumoto K, Horie S, Takayama H, et al. Antinociception, toler-
25. Schwartz S, Etropolski MS, Shapiro DY, et al. A pooled analysis ance and withdrawal symptoms induced by 7-hydroxymitragynine,
evaluating the efficacy and tolerability of tapentadol extended re- an alkaloid from the Thai medicinal herb Mitragyna speciosa. Life
lease for chronic, painful diabetic peripheral neuropathy. Clin Drug Sci. 2005;78:2‐7.
Investig. 2015;35:95‐108. 37. Matsumoto K, Hatori Y, Murayama T, et al. Involvement of mu-
26. Wade WE, Spruill WJ. Tapentadol hydrochloride: a centrally acting opioid receptors in antinociception and inhibition of gastrointestinal
oral analgesic. Clin Ther. 2009;31:2804‐2818. transit induced by 7-hydroxymitragynine, isolated from Thai herbal
27. Stegmann JU, Weber H, Steup A, Okamoto A, Upmalis D, Daniels S. medicine Mitragyna speciosa. Eur J Pharmacol. 2006;549:63‐70.
The efficacy and tolerability of multiple-dose tapentadol immediate 38. Raffa RB, Beckett JR, Brahmbhatt VN, et al. Orally active
release for the relief of acute pain following orthopedic (bunionec- opioid compounds from a non- poppy source. J Med Chem.
tomy) surgery. Curr Med Res Opin. 2008;24:3185‐3196. 2013;56:4840‐4848.
28. Kwong WJ, Hammond G, Upmalis D, Okamoto A, Yang M, Kavanagh 39. Raffa RB. On subclasses of opioid analgesics. Curr Med Res Opin.
S. Bowel function after tapentadol and oxycodone immediate re- 2014;30:2579‐2584.
lease (IR) treatment in patients with low back or osteoarthritis pain.
Clin J Pain. 2013;29:664‐672.
29. Hartrick C, Van Hove I, Stegmann JU, Oh C, Upmalis D. Efficacy and
How to cite this article: Raffa RB, Pergolizzi JV Jr, Taylor R Jr,
tolerability of tapentadol immediate release and oxycodone HCl
Ossipov MH. Nature’s first “atypical opioids”: Kratom and
immediate release in patients awaiting primary joint replacement
surgery for end- stage joint disease: a 10-day, phase III, random- mitragynines. J Clin Pharm Ther. 2018;00:1–5.
ized, double-blind, active-and placebo-controlled study. Clin Ther. https://doi.org/10.1111/jcpt.12676
2009;31:260‐271.