Therapeutic uses of Amphetamine?

1 Introduction

1.1 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.

1.2 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.

1.3 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.

2 Amphetamine and Pain Relief

2.1 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).

2.2 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.

2.3 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".

2.4 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.

2.5 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."

2.6 Human Studies: In 1979, Shimm et al studied pain management in chronic cancer patients and 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.

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

2.8 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.

2.9 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."

2.10 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."

2.11 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."

2.12 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.

2.13 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..."

3 Amphetamine and Intestinal function.

3.1 Amphetamine boosts the sympathetic (autonomic) nervous system in a similar way to adrenaline, affecting many areas of the bodily functions in addition to psychoactive and central nervous system effects. Increased sympathetic activity reduces gut motility, whereas parasympathetic activity increases it.

3.2 Cocaine and amphetamine-regulated transcript peptides (CART) are found in areas of the intestines, and are thought to be responsible for regulating the sympathetic nervous system effects. Amphetamine has been shown to block stimulation of intestinal activity by some neurotransmitters, but not others: "d-amphetamine may act as an antagonist to TRH without influencing the movement of calcium ions in smooth muscle or muscarinic receptors and that contractile responses to TRH-A are mediated through TRH receptors in the myenteric cholinergic nerves."

3.3 Beyer et al reported a case history of ischaemic colitis associated with use of oral (dextro)-amphetamine and other sympathomimetic agents, causing abdominal pain and rectal bleeding. A 1972 Polish study examined the effects of chronic amphetamine exposure on the digestive tract in rats. It has not been possible to obtain a translated copy, or further details, of this study at the present time.

4 Summary - Amphetamine as Medcine

4.1 Pain: 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).

4.2 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.

4.3 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.

4.4 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).

4.5 GI Tract: Amphetamine may reduce the symtoms of gastrointestinal disturbance by reducing motility of the gut.

4.6 There is insufficient evidence to determine whether or not amphetamine may directly benefit coeliac disease, or whether it may exacerbate the condition. No such studies have been published in medical or scientific journals over the past 25 years.