Cannabis is a term that describes products derived from the Indian hemp, Cannabis sativa. It has its origins probably in India but now grows all over the world. The chemical compounds responsible for intoxication and medicinal effects are found mainly in a sticky golden resin exuded from the flowers of the female plants and surrounding leaves. Cannabis sativa contains a wide range of different chemicals including a family of compounds called “cannabinoids”. Of the cannabinoids delta-9 tetrahydrocannabinol (THC) is probably the main compound responsible for the psychotropic activities.
Cannabis has been used as a medicine for thousands of years and is mentioned in a Chinese herbal dating back to 2700 BC. There are records of ’its medicinal use in Egyptian papyri of the sixteenth century BC. Much later, the plant is mentioned in Assyrian texts and in Greek and Roman sources as a medicinal agent.
Early Experiences in the 19th Century
Cannabis Tincture was used in the nineteenth century as an analgesic, as well as numerous other conditions and was considered milder and less dangerous than opium. W.B.O’Shaughnessy was the first of the western physicians to take an interest in cannabis as a medicine on account of his observations on its use in India at the time and was the main figure behind its resurgance. He not only meticulously recorded the popular and medical uses of the various preparations in India but also conducted animal and human experiments and applied his knowledge in the clinic (O’Shaugnessy, 1841, 1843). In 1845 Donovan found cannabis to be highly effective in cases of violent neuralgic pain in the arms and fingers, inflammation of the knee, facial neuralgia and sciatica affecting the hip, knee and foot (Donovan, 1845). The most detailed review of the therapeutic uses of cannabis in the mid-19th Century was from Christison who reports uses of the tincture for rheumatic pain, sciatica and toothe ache (Christison, 1851).
An article written by Dr. J.Russell Reynolds (physician to Queen Victoria) noted, “In almost all painful maladies I have found Indian Hemp by far the most useful of drugs.” Dr. Reynolds cites neuralgia, facial pain and neuritis as being particularly responsive to cannabis. He also wrote: “Migraine: Very many victims of this malady have for years kept their suffering in abeyance by taking hemp at the moment of threatening, or onset of the attack.”
Hundreds of articles were written in European and American journals on the use of cannabis for many types of pain; but around 1890 the use of cannabis started to decline. There are several reasons that probably contributed to this decline: the increasing availability of injectable opiates; the uncontrollable variability in strength and composition of the cannabis preparations; the unpredictable response of patients to cannabis taken orally; and the introduction of aspirin, chloral hydrate and the barbiturates.
The Law Exerts its Control
In 1928 cannabis was banned for non-medicinal purposes in the UK. In America in 1937 a marihuana tax was introduced to discourage recreational use of cannabis and the tight controls in both countries served to discourage its use medicinally. In 1954 and 1957 the World Health Organisation (WHO) affirmed its view that cannabis had no therapeutic value. In 1968, the UN Economic and Social Council adopted a resolution recommending that all countries concerned should intensify enforcement of restrictions on traffic and use, that they promote research and deal effectively with publicity advocating legalisation or tolerance to the non medical use of the drug.
In 1969, the WHO reported cannabis as not physically habit-forming but as a drug of dependence and recommended keeping it under legal control. By 1960 in America and 1971 in the UK, cannabis was made a Schedule 1 drug making possession and medicinal use illegal without a special licence. This severely restricted clinical research.
The Purification, Analysis and Understanding of Cannabis
In 1964 THC was obtained in its pure form and the structure elucidated (Gaoni and Mechoulam, 1964). Lilly Research Laboratories, in 1968 initiated a cannabinoid research program. Early clinical studies investigated the pharmacological actions of THC and synthetic analogues. The objective was to derive a compound with the benefits of cannabis but without the adverse effects. As a result nabilone came to the forefront and was marketed as an anti emetic in Canada in 1982 and the UK in 1983.
On May 13, 1986, the Drug Enforcement Administration (DEA) in America transferred a synthetic form of THC from Schedule 1 to Schedule 2 for use as an antiemetic for cancer patients undergoing chemotherapy. In effect, this action by the DEA resulted in a dual scheduling of an identical molecule. A molecule of THC derived from the cannabis plant is a schedule 1 molecule, since the definition of “cannabis” includes all derivatives of the plant; but an identical molecule when synthetically derived and encapsulated in a gelatin capsule, is a Schedule 2 molecule.
In 1988 in America, an Administrative Law Judge stated cannabis to be “…one of the safest drugs known to man.” The DEA overruled this and in 1992 gave its final rejection to the medicinal use of cannabis. In the same year, Hewlett in St Louis USA discovered the first cannabinoid receptor in neuronal tissue (Devane et al., 1988) which led to the discovery of the first endogenous ligand anandamide, the body’s own natural cannabinoid in 1992 ().
The Physiology of Acute and Persistent Pain
Pain protects the body from external harm and prevents activity after damage due to trauma and surgery, while it heals. It is also the result of many pathological processes.
To most people the mechanism is similar to an electrical alarm system but this is much too simplistic.
Steps in Pain Perception
Nociceptors (pain receptors) are present in the skin and most other tissues. They respond to mechanical, thermal or chemical stimulation. The chemical stimulation is due to a variety of substances released into damaged tissues, for example prostaglandins and bradykinin. Sensation is carried to the spinal cord either by “fast” fibres, which detect sharp, localised, short-lived pain, or by “slow” fibres, which carry signals of diffuse, ongoing pain.
Wind up is a normal process in which peripheral and central neurones become sensitised, leading to amplification of signals. The painful area may become hypersensitive to touch. The understanding of this process is still being worked out but it involves a complex chain of neurochemical events.
Pain is transmitted up the spinal cord into the brain. This invokes an interaction of arousal, perception, emotion, interpretation and memory. It also triggers physiological changes. The transmission of pain signals across millions of neurones is mediated by neuropeptides, including beta-endorphin, enkephalin, dynorphine, serotonin and other catecholamines, these enhance or inhibit transmission.
There is a descending system of nerves through the spinal cord back to the dorsal horn cells which can inhibit or enhance the pain perceived. Various neurotransmitters are involved. Descending inhibition damps down incoming pain impulses, providing analgesia. It operates when, for example, someone is injured but feels no pain until away from the site of danger. Inhibitory signals travel from the brain down the spinal cord and “damp down” incoming pain impulses. Similarly pain may be increased. This is the mechanism by which for example, happiness or distraction will reduce pain, whilst depression, anxiety or sleeplessness will aggravate it.
The concept of the “gate” was introduced in 1966 by Melzak and Wall to explain the processing of pain in the dorsal horn of the spinal cord. The wider the gate is open, the more signals are transmitted. The most important control of the gate comes from the brain itself, mediated through the descending pathways described above. From the periphery, touch can be used to close the gate (e.g. transcutaneous nerve stimulation, rubbing, massage). However, in the acute situation touch may have the opposite effect and intensify pain perception.
The nervous system is plastic in both acute and chronic pain. Nerve cells can change the quantity and type of transmitter that they release, receptors can change their activity and new synapses can develop.
Cutting or Damaging a Nerve
Damage to a peripheral nerve can cause major changes in cell function at all levels through to the cerebral cortex. These changes may be permanent, so the idea that a nerve can simply be cut to control pain is incorrect.
Analgesics and How They Work
Analgesics affect the transmission of pain in a wide variety of ways and places and are categorised in the following way:
NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen and indomethacin, have anti-inflammatory activity inhibiting the formation of prostaglandins from arachidonic acid via the cyclooxygenase pathway. Their main site of action is in the periphery at the site of tissue damage but there may also be an effect within the spinal cord. Paracetamol is a paraaminophenol derivative with analgesic and antipyretic activity but no anti-inflammatory activity, with the spinal cord as its site of probable action. Opioid analgesics such as morphine and pethidine act on specific receptors on the descending pathways to inhibit pain. The main mode of action is by pre — and post-synaptic inhibition thereby preventing transmission of neural signals to the brain.
Antidepressants modulate the response to pain within the brain and spinal cord. It has been suggested that the analgesic action of tricyclic antidepressants and monoamine oxidase inhibitors is mediated by their action on central neurotransmitter functions; particularly serotonin and noradrenaline pathways. Anticonvulsants affect the abnormal triggering and transmission of pain along nerve fibres by acting as membrane stabilisers. Carbamazepine is the most often prescribed, although sodium valproate, clonazepam and clobazam are also used.
A wide range of agents are being explored nowadays, targeted on the various steps in the complex pathway of the transmission of pain. Agents such as clonidine, baclofen and ketamine are being used and their roles evaluated.
It is against this background that the pharmacological and clinical investigations of the cannabinoids will now be discussed.
So far, two types of cannabinoid receptor, CB1 and CB2, have been identified. The CNS responses to the cannabinoids are likely to be via the CB1 receptor, as evidence for the presence of the CB2 receptor has only been found in the spleen. The CB1 receptor was the first to be identified and has since been cloned. It has been found in rat brain, with the greatest abundance being in the cortex, cerebellum, hippocampus and striatum, with a lesser concentration in the brain stem and spinal cord ().
Certain of the in-vitro effects seen with the cannabinoids may not be mediated by a receptor mechanism. The lipophilic nature of the cannabinoid compounds results in significant changes in the “fluidity” of phospholipid containing membranes and this may be the property responsible for the altered responses of membrane-associated enzymes and proteins. The mechanism of action is comparable to the steroid anaesthetic, alphaxolone and the volatile anaesthetic halothane. However THC produces considerably less fluidization than alphaxolone, thus explaining the lack of clinical anaesthesia. The psychotropically inactive, cannabidiol produces an opposite effect: a decrease in the molecular disorder of the lipid bilayer. Apart from the evidence that cannabinoids can alter the physical properties of membranes there is also evidence that THC can alter the composition of the membranes within the brain and affect the biosynthesis of membrane lipids ().
Laboratory Evidence for Cannabinoid Analgesic Activity
From the large number of methods available for evaluating the effectiveness of analgesics, it is clear that the optimal tool for estimating pain and pain perception is lacking; however, a comprehensive picture can be obtained by using several testing procedures. Experiments with rats and mice have shown that some cannabinoids are effective analgesics in a number of standard tests which are used to evaluate drug analgesic activity, examples of which are:
The Tail-Flick Test
This involves shining a ray of light on the tail of a mouse and measuring the time taken before the mouse moves its tail out of the way. Analgesics would increase the time before the tail would be flicked away (). Buxbaum et al. () have reported that with intraperitoneal administration in male Sprague — Dawley rats, THC was comparable to morphine in the rat tail-flick test.
Bisher and Mechoulam () reported that 20mg/kg THC intraperitoneally produced activity in the mouse tail-flick test equivalent to that produced by 10mg/kg morphine sulphate administered subcutaneously. Dewey et al. () found no activity with THC below 100mg/kg.
The Hot Plate Test
Mice are placed on a plate maintained at 55°C and the time taken before they lick their paws or jump is measured. Analgesics increase this time interval. The mice are not left on the plate for more than 30 seconds (). Sofia et al. () found oral administration of THC to be equivalent to morphine in the hot plate test.
The Abdominal Stretching Test
Mice are injected intraperitoneally with p-phenylquinone and the number of stretches recorded over a one minute period. Analgesics would tend to decrease the number of stretches (). THC reduces the number of abdominal stretches but is not as effective as morphine ().
Carrageenan Induced Oedema Test
In this study, carrageenan is injected into the paws of rats to create oedema. THC was found to be 20 times more potent than aspirin and twice the potency of hydrocortisone in reducing the volume of the oedema. ().
Acetic Acid Abdominal Constriction Test
0.25ml of acetic acid 0.5% is injected intraperitoneally in rats and the number of constrictions over 5 minutes counted. THC was found to be 10 times more potent than aspirin in reducing the number of constrictions ().
Haffner’s Tail Pinch Test
An artery clip is placed on the tail of a rat and the time taken for the rat to bite at the clip measured. THC was found to be a very effective analgesic at 11 mg/kg orally where as no analgesia was seen with aspirin at 300mg/kg ().
There are many reports of analgesic tests in animals using cannabis or THC and all have varying results (). This may be due to the species used in the experiment or even the housing conditions before and during the experiment. In each case the end point depends upon the expertise of the assessor in evaluating a certain reaction made by the animal in response to the stimulus, whether it be a squeal, head jerk, tail flick, licking of paws or jumping.
Anecdotal Evidence for Cannabinoids in Pain Relief
There is a growing body of contemporary anecdotal evidence for the benefits of cannabis in pain relief; there are currently four pain problems where cannabinoids seem to be of most benefit.
Here there may be widespread damage to the nervous system and alterations to the neurochemistry. The effects of the disease are very variable. Up to 40% of patients with multiple sclerosis experience pain and this is often unresponsive to conventional analgesics including opiates, anti-depressants and anticonvulsants. Many also get painful bladder spasms which seem particularly responsive to cannabis.
Major Spinal Injury
Traumatic spinal injury up to and including tetraplaegia, may cause significant pain below the level of injury or at the level itself. This pain is due to disruption of pain control mechanisms at the level of spinal cord damage. De-afferentation may be leading to a loss of inhibitory control in pain systems (pathways) in higher parts of the central nervous system.
Other Neurogenic Pain
There are other situations where nerves may be damaged, either traumatically or as a result of various disease processes (e.g. diabetes). The pain produced may be uncontrollable with conventional analgesic practise.
Traumatic Spinal Strains/Sprains
Some musculo-skeletal injuries remain resistant to conventional analgesics up to and including morphine. They are often associated with significant muscle spasm.
The evidence that cannabinoids are effective in these groups of patients is drawn from the experience of the patients themselves with the use of cannabis, usually when smoked. Naturally patients are very reluctant to admit to using an illegal drug. It is therefore impossible to establish a profile for use and effectiveness of cannabis at present.
There is also evidence from the use of the drug nabilone, a synthetic cannabinoid. Currently nabilone is only licensed for use as an anti-emetic during chemotherapy and for short-term use. There is no data on its clinical use in pain control nor is there data on its long term use. Some patients who have gained benefit from the illicit use of cannabis have elected to try nabilone. All patients have persistent (chronic) pain and have obtained little or no benefit from their current therapy. Some are taking a “cocktail” of medications and nearly all wish to discontinue their reliance on them for what is often minimal benefit. Many of these drugs have significant dependency potential, for example opiates and anti-depressants.
Long standing (chronic) pain is a common phenomenon affecting possibly as many as one person in twelve. Conventional analgesic practice is by no means universally effective. Cannabis could significantly improve our ability to help these patients.
The Experience of an Ms Patient Who Uses Cannabis
CH (A multiple sclerosis patient) writes of her experiences:
“It was hard enough to deal with all the problems that multiple sclerosis has brought me during the past 10 years, but it became much more difficult when I realised I had to cope with the unpleasant side-effects of my medication as well. I was being prescribed a whole range of medicines. There were pills to stop me feeling sick. These made me clumsy and drowsy. There were pills to relieve my bladder spasms but they made me feel sick and gave me blurred vision. There were pills to help me sleep but they made me anxious and were habit forming.
Then a friend showed me an American article about the growing number of people with MS who had found safe and effective relief from their symptoms by taking cannabis. I could not see what I had to lose, so I decided to see if it would work for me too.
I am a middle-aged suburban housewife living in the north of England and have two young children. I am not remotely involved in the “drug scene”. It took me some time, difficulty and expense to lay my hands on this illegal substance. When I had got it, I had no idea how to find out how much I should take and when. The doctors who see me were all interested and supportive but they didn’t know much about it either, so I had to work everything out for myself. For about a year now, I have been regularly taking a small amount of cannabis resin — less than the size of a pea — late at night. I used to smoke it with dried herbs (not tobacco), but I worried that my children might see me smoking, so now I eat it. After a short time my body completely relaxes, which relieves my tension and spasms. During the day I have to use a catheter when ever I want to empty my bladder and most notably, cannabis relieves the discomfort and difficulty I have controlling it. It has also stopped the nausea that kept me awake at night. It is hard to regulate the dose. The quality varies, and, I suppose, like alcohol, the same amount on different occasions can have different effects.
Over the months I found I was able to reduce the doses of standard medication and now take none at all. I don’t often take enough to “get high”. When I do, I’m sure the feeling of calm and euphoria does my spirits a lot of good. Like many people who are ill, it is only too easy to become introspective and self-pitying. It is neither easy nor pleasant for me to obtain supplies, but I am happy to carry on as it does me so much good. I don’t like breaking the law, I would far rather be able to obtain it from the chemist’s”.
Side Effects of Cannabis and Nabilone
Cannabis produces a very wide range of effects in human behavior. It produces euphoria, anxiety, lethargy, drowsiness, impaired performance, memory defects, changes in perception of time and depersonalization. These effects do vary between subjects and can also depend on factors such as the subject’s pre-existing mood state, the social setting in which the cannabis is taken and whether the patient has taken cannabis before. The most common physical side effects of cannabis are a reddening of the eyes and a slight increase in the heart rate. Neither of these is reported to be uncomfortable or dangerous. Propranolol can prevent the tachycardia but does not affect the subjective and behavioral effects.
Balanced against these side effects it must be remembered that after so many years of use through history there is still no credible evidence that cannabis has ever caused a single death.
Clinical trials with nabilone showed that nearly all patients experienced at least one side effect. The most common being drowsiness followed by dizziness, euphoria, dry mouth, ataxia, visual disturbances, concentration difficulties, sleep disturbance, dysphoria, hypotension, headache and nausea (in decreasing order of incidence). Other reported side effects include confusion, disorientation, hallucinations, psychosis, depression, decreased co-ordination, tremors, tachycardia, decreased appetite and abdominal pain. Tolerance to drowsiness and euphoria develops rapidly without any noticeable drop in analgesic capability.
Patients who have taken nabilone 2 mg each day for several months and then stopped, have not reported any withdrawal symptoms; when restarted, tolerance to the drowsiness has to be re-acquired. Nabilone may impair mental and/or physical abilities when operating machinery or driving a car, and so patients must be made aware of this. Some patients at the James Paget Hospital have found nabilone to be excellent at reducing their pain but have been unable to continue treatment because they need to drive. The effect of nabilone may persist for a variable and unpredictable period of time following oral administration and side effects have been known to persist up to 72 hours after stopping the drug. Slight changes in mood and personality can occur in a few patients. This is usually noticed by the patient’s partner.
Laboratory studies have so far shown no evidence of teratogenicity, but no controlled studies have been carried out in pregnant women. Nabilone can elevate supine and standing heart rates and cause postural hypotension. It should therefore be used cautiously in the elderly and in patients with hypertension and heart disease.
The Future for Cannabis as a Drug for Pain Relief
Pharmacologically, cannabis is referred to as a “dirty drug”. It contains many active compounds that have many effects, the mechanisms of which are barely known. It is tempting to consider all these compounds a hindrance to development; but they must be thought of as exciting opportunities. A major advantage of cannabis is its safety and low potential for physical dependency. The disadvantages are the side effects, its reputation and its legal status, which inhibits research.
Separating the analgesic activity of the cannabinoids from their significant side effects has been long sought. In the 1970s, Wilson and May suggested that separation was possible which spurred plenty of interest (). Unfortunately the only separation achieved so far is to produce derivatives that still maintain the psychopharmacological effects but have no analgesic properties. ()
It is known that THC has an analgesic effect, but there are many other cannabinoids in cannabis that can contribute to its pain relieving effects. Cannabidiol, which is devoid of cannabimimetic effects is a potent cyclooxygenase inhibitor and analgesic but has been overlooked as studies have concentrated on THC and its derivatives. Metabolites of the cannabinoids may be contributing to the analgesia by an indirect route, e.g. by increasing the permeability of the blood brain barrier to other mediators.
There are problems associated with the design of clinical trials of these agents. Pain relief is a subjective sensation and is more difficult to evaluate than for example, blood pressure. Obtaining consistent samples of cannabis is a problem.
The ideal derivative would be crystalline, stable at room temperature, soluble in water and have the beneficial effects of the cannabinoids but none of the side effects. A suitable pharmaceutical form would preferably have the rapid effects of smoking cannabis. Possibilities could be a cannabinoid in an aerosol preparation which could incorporate Patient Controlled Analgesia technology, thereby regulating the rate of delivery.
There is only one route forward for the advancement of the medicinal use of cannabis for pain relief and it is the slow route followed by all other prospective drugs; to identify all the active components of the cannabis plant (smoked and unsmoked), isolate them and carry out properly planned clinical trials with a suitable route of delivery. Cannabis and nabilone are unlikely to have a dramatic part in the physician’s repertoire of analgesics as a whole, but it will provide pain relief in some cases when all else has failed.
Selections from the book: “Cannabis. The Genus Cannabis”. Edited by David T.Brown. Series: “Medicinal and Aromatic Plants — Industrial Profiles”. 1998.