Dr. DeLuca's Addiction Website

Amphetamine and Analgesia

The Independent Drug Monitoring Unit (I.D.M.U. LTD) is an independent research consultancy conducting original research, including large-scale surveys of drug users, and providing expert evidence to the courts in criminal cases involving controlled drugs.

British National Formulary 35 (March 1998) p186

http://www.idmu.co.uk/amphetpain.html 


Introduction

Amphetamine was widely prescribed until the mid 1960s as a stimulant and appetite-suppressant, until the dependence-potential of amphetamine (and other stimulants) led to a falling out of favour among the medical profession. Amphetamine, although a controlled drugs, is still prescribable for certain conditions (e.g. narcolepsy), and appears in Schedule 2 of the Misuse of Drug Regulations 1985, meaning that it can be prescribed for medical treatment subject to proper monitoring and reporting criteria.

Amphetamine is a powerful central nervous system stimulant drug, used recreationally for the euphoriant effects, as well as ‘functionally’ to ward off fatigue and increase energy and capacity for physical activity. The effects of amphetamine are similar to those of cocaine, both affecting the same neural systems, amphetamine stimulates catecholamine release, and cocaine reduces reuptake - expressed simply, if the level of alertness were to be represented by the water level in a bath, amphetamine would act by turning on the taps, whereas cocaine would act by putting in the plug.

The effects of amphetamine have been studied for over a century, although since it became a controlled drug in most countries of the world, opportunities for research on the effects on humans have been limited. 


Animal Studies

Animal studies have consistently found stimulant drugs such as amphetamine and cocaine may cause analgesia (typically measured by the length of time an animal takes to respond to a painful stimulus). 

Mice: Natsuoka et al reported "analgesic actions ((of amphetamines) involve the participation of endogenous serotonin and endogenous opioid peptides" Furst suggested a relationship between the stimulant neurotransmitter systems and opiate analgesia. A Russian study suggests the analgesic effects may be influenced by psychosocial factors. Amphetamine was found to decrease depression of swimming endurace in mice treated with opiates, suggesting the (similar/synergistic) analgesic effects may be differentiated from the (opposite/antagonistic) psychoactive effects of the two drug types. As with humans, tolerance to the analgesic effects of both amphetamine and morphine are reported in mice. 

Rats: Studies in rats have suggested amphetamine-like compounds can induce analgesic (pain-killing) effects potentiating the analgesic effects of opiates, and that analgesia from amphetamine may be counteracted by dopamine antagonists - Clarke et al concluded: "dopamine innervation of the nucleus accumbens... plays a major role in the analgesic effect of amphetamine" - or by destroying the dopamine-producing cells in brain-stem nuclei. However, earlier studies suggested noradrenaline rather than dopamine to be the mediating neurotranmitter for amphetamine enhancement of opiate analgesia, that amphetamine analgesia did not involve endogenous opiates such that "amphetamine possesses intrinsic analgesic properties". 

The contrasting effects on alertness of opiates and amphetamines have been widely-noted: Borisenko, studying behavioural effects and pain relief from opiates and amphetamine, reported "the analgetic action and that activating the positive emotion were independent effects of the psychotropic agents.". The reversal of narcotic-induced depression by amphetamine was also noted by Malec et al and Lakin Et al. Miksic et al considered there to be two distinct neural mechanisms underlying the effects of analgesia and euphoria.

Sasson et al considered in 1986 that "opiate analgesia is potentiated by concomitant d-amphetamine administration. The mechanisms involved in this potentiation warrant further investigation for the clinical management of pain."

Human Studies

In 1979, Shimm et al studied pain management in chronic cancer patients anc concluded "Stimulants such as cocaine and amphetamines both potentiate narcotic analgesia and reduce narcotic-induced somnolence and respiratory depression" A 1967 study found the analgesic affect of aspirin to be modified by amphetamine.

Studying healthy male volunteers, Webb et al found amphetamine and a non-opiate analgesic both increased pain thresholds, the combination providing the greatest relief.

Jaskinski et al found the combination of amphetamine and morphine to create greater euphoria among substance-abuser than either drug alone, although the psychological effects (stimulation, drowsiness) were mutually attenuated, considering there to be a greater degree of abuse potential from the combination of the two drugs.

In a treatise on cancer pain, Mancini et al reported: "Many drugs, such as nonsteroidal antiinflammatory agents, tricyclic antidepressants, corticosteroids, benzodiazepines, amphetamines, antiemetics, oral local anesthetics and bisphosphonates have been suggested to have adjuvant analgesic effects."

Dalal et al commented: "Studies with human subjects have confirmed the enhancement of opioid analgesia by amphetamines and, in addition, have demonstrated that psychostimulant drugs produce a decrease in somnolence and an increase in general cognitive abilities. The greater cognitive alertness, moreover, allows the use of larger opioid doses, which can produce a substantial increase in analgesia."

Reich et al observed: "amphetamines... have been rarely used in the past, but have been recently introduced in the palliative treatment in oncology. They have stimulating, antidepressive and perhaps coanalgesic effects. They can alleviate sleepiness related to opiates analgesics which are given in chronic pain."

A study of female migraine patients found they were significantly more likely than controls to be using amphetamine, although the authors did not indicate whether this was considered a causative factor or an attempt at self-medication.

Following a clinical study of cancer patients in Bristol, O’Neill concluded: "Adjuvant analgesic drugs and non-drug measures should be used whenever possible, and drugs should be chosen that will not contribute to existing difficulties. The appropriate use of psychostimulants has yet to be established..."

A retrospective Swedish study suggested that nitrous oxide analgesia during childbirth may contribute to amphetamine addiction later in life.


Summary

It is well-established within the scientific literature that amphetamine can provide an analgesic (pain killing) effect in its own right, and enhance the analgesic effects of opiate painkillers (e.g. morphine, codeine).

Recent developments in the treatment of the terminally ill suggests amphetamines may have a role to play in the management of severe pain as an adjunctive therapy, by enhancing the effects of opiates. However, this role is limited in long-term use by the high degree of tolerance and dependence which frequently develops with prolonged stimulant use.

Opiates are likely to cause drowsiness, reduced alertness and impaired cognitive function - effects which are reduced or reversed by amphetamine. The risk of respiratory depression with high doses of opiates is also reduced with amphetamine, allowing larger doses pain-relief.

The analgesic role of stimulant drugs is thought to mimic the effects during stress, where pain (e.g. from an injury) is not experienced during crises such as armed combat or other potentially life-threatening events (such effects are even reported in sporting contests).

Amphetamine and Cannabis: No scientific studies have been found investigating the extent to which the analgesic effects of cannabis and amphetamine may be related, nor as to any interactions between the combined effects of these drugs on analgesia or pain thresholds (i.e. whether the combined effects are synergistic, additive, neutral or antagonistic compared to either drug alone). This is clearly an area where further research is needed.

 

References:

Ahmed SS, Joglekar GV, Balwani JH (1966) Potentiation of the analgesic effect of codeine in rats by d-amphetamine. Arch Int Pharmacodyn Ther 1966 Jan;159(1):185-8

Nott MW (1968) Eur J Pharmacol Potentiation of morphine analgesia by cocaine in mice.5(1):93-9

Connor J, Makonnen E, Rostom A (2000) Comparison of analgesic effects of khat (Catha edulis Forsk) extract, D-amphetamine and ibuprofen in mice.J Pharm Pharmacol 52(1):107-10

Piercey MF, Moon MW, Blinn JR, Dobry-Schreur PJ (1986) Analgesic activities of spinal cord substance P antagonists implicate substance P as a neurotransmitter of pain sensation. Brain Res 385(1):74-85 

Natsuoka Y, Sakuma M, Uruno T, Kubota K (1984) Characteristics of analgesia induced by noncatecholic phenylethylamine derivatives: possible involvement of endogenous opioid peptides and serotonin in phenylethylamine analog-induced analgesia. Jpn J Pharmacol 34(3):277-87 

Furst Z (1973) [Relationship between narcotic analgesics and adrenergic transmission]. [Article in Hungarian] Acta Pharm Hung 43(3):180-9

Vekovishcheva OIu, Zvartau EE (1999) [The reactivity of laboratory mice in pharmacological tests as dependent on their zoosocial status].[Article in Russian] Eksp Klin Farmakol 62(1):6-10 

Richards RK (1975) A study of the effect of d-amphetamine on the toxicity, analgesic potency and swimming impairment caused by potent analgesics in mice. Arch Int Pharmacodyn Ther 216(2):225-45 

Little HJ, Rees JM (1974) Tolerance development to the antinociceptive actions of morphine, amphetamine, physostigmine and 2-aminoindane in the mouse. Experientia 30(8):930-2

Abbott FV, Guy ER (1995) Effects of morphine, pentobarbital and amphetamine on formalin-induced behaviours in infant rats: sedation versus specific suppression of pain. Pain 62(3):303-12 

Naik SR, Pradhan RJ, Sheth UK (1972) Effect of amphetamine on tremorine analgesia in mice. Indian J Med Res 1972 Sep;60(9):1328-31 

Major CT, Pleuvry BJ, Rees JM (1970) A comparison of the analgesia produced by morphine and the sympathomimetic drugs. Br J Pharmacol 40(1):143P+

Nicak A (1965) The influence of serotonine and amphetamine on analgesic effect of morphine after reserpine premedication in rats and mice. Med Pharmacol Exp Int J Exp Med 13(1):43-8

Nencini P, Fraioli S, Pascucci T, Nucerito CV (1998) (-)-Norpseudoephedrine, a metabolite of cathinone with amphetamine-like stimulus properties, enhances the analgesic and rate decreasing effects of morphine, but inhibits its discriminative properties. Behav Brain Res 92(1):11-20 

Franklin KB (1989) Analgesia and the neural substrate of reward. Neurosci Biobehav Rev 13(2-3):149-54 

Altier N, Stewart J (1998) Dopamine receptor antagonists in the nucleus accumbens attenuate analgesia induced by ventral tegmental area substance P or morphine and by nucleus accumbens amphetamine. J Pharmacol Exp Ther 285(1):208-15 

Clarke PB, Franklin KB (1992) Infusions of 6-hydroxydopamine into the nucleus accumbens abolish the analgesic effect of amphetamine but not of morphine in the formalin test. Brain Res 580(1-2):106-10 

Morgan MJ, Franklin KB (1990) 6-Hydroxydopamine lesions of the ventral tegmentum abolish D-amphetamine and morphine analgesia in the formalin test but not in the tail flick test. Brain Res 1990 Jun 11;519(1-2):144-9 

Izenwasser S, Kornetsky C (1988) Potentiation of morphine analgesia by D-amphetamine is mediated by norepinephrine and not dopamine. Pain 33(3):363-8 

Drago F, Caccamo G, Continella G, Scapagnini U (1984) Amphetamine-induced analgesia does not involve brain opioids. Eur J Pharmacol 101(3-4):267-9 

Borisenko SA (1976) [Mechanism of the analgesic effect of narcotic analgetics].[Article in Russian] Biull Eksp Biol Med 81(4):432-4 

Malec D, Fidecka S, Langwinski R (1977) Central action of narcotic analgesics. I. Catalepsy and stereotypy in rats and narcotic analgesics. Pol J Pharmacol Pharm 1977 May-Jun;29(3):177-93

Lakin ML, Winters WD (1978) Behavioral correlates of naloxone inhibition of analgesia induced by various CNS excitatory drugs in the rat. Proc West Pharmacol Soc 21:27-30 

Miksic S, Shearman GT, Lal H (1980) Differential enhancement of narcotic discrimination and analgesia by amphetamine and haloperidol: an evidence for distinct mechanisms underlying analgesia and euphoria. Subst Alcohol Actions Misuse 1(3):281-5

Sasson S, Unterwald EM, Kornetsky C (1986) Potentiation of morphine analgesia by d-amphetamine. Psychopharmacology (Berl) 90(2):163-5 

Shimm DS, Logue GL, Maltbie AA, Dugan S (1979) Medical management of chronic cancer pain. JAMA 241(22):2408-12 

Kulkarni SD, Joglekar GV, Balwani JH (1967) Modification of aspirin analgesia by amphetamine. J Exp Med Sci 1967 Jun;11(1):14-7 

Webb SS, Smith GM, Evans WO, Webb NC (1978) Toward the development of a potent, nonsedating, oral analgesic. Psychopharmacology (Berl) 60(1):25-8 

Jasinski DR, Preston KL (1986) Evaluation of mixtures of morphine and d-amphetamine for subjective and physiological effects. Drug Alcohol Depend 17(1):1-13 

Mancini I, Body JJ (1998) [Treatment of cancer pain: the role of co-analgesics].[Article in French] Rev Med Brux 19(4):A319-22

Dalal S, Melzack R (1998) Potentiation of opioid analgesia by psychostimulant drugs: a review. J Pain Symptom Manage 16(4):245-53

Reich MG, Razavi D (1996) [Role of amphetamines in cancerology : a review of the literature].[Article in French] Bull Cancer 1996 Nov;83(11):891-900 

Chen TC, Leviton A, Edelstein S, Ellenberg JH (1987) Migraine and other diseases in women of reproductive age. The influence of smoking on observed associations. Arch Neurol 44(10):1024-8 

O'Neill WM (1994) The cognitive and psychomotor effects of opioid drugs in cancer pain management. Cancer Surv 1994;21:67-84 

Jacobson B, Nyberg K, Eklund G, Bygdeman M, Rydberg U (1988) Obstetric pain medication and eventual adult amphetamine addiction in offspring. Acta Obstet Gynecol Scand 67(8):677-82 


Alexander DeLuca, M.D., FASAM.
Copyright © 1999. All rights reserved.                            [Top of Page]
Revised: June 16, 2001.
Dr. DeLuca's Addiction Website