CANNABIS AND PAIN MANAGEMENT

The following article is an edited composite of a Policy Paper on
Cannabis in Pain Treatment presented to the American Academy of Pain
Management by Dr Ethan Russo, MD

Effective treatment of acute, chronic and intractable pain is a
critically important public health concern in the world today. Despite
a vast array of analgesic medicines including anti-inflammatory and
opioid analgesics, countless patients continue to suffer the burden of
unrelieved pain. Opiate addiction, and the recent OxyContin
controversy underline the importance of newer effective and safe
alternatives.

For over a century, international commissions have studied the issue
of cannabis, and virtually uniformly recommended its decriminalization
and provision for medical applications, specifically including the
treatment of pain.

Cannabis has been employed as an analgesic for thousands of years, and
was utilized in this country as well, particularly for neuropathic
pain, prior to its effective removal from the American market 65 years
ago. Historical cannabis supporters have included such physicians and
scientists as Galen, Dioscorides, Parkinson, Linnaeus, Gowers, Weir
Mitchell, Osler, Solomon Snyder, and many others. Cannabis remains a
frequently employed ethno-botanical agent in pain management among
indigenous peoples of the world.

Modern research on endogenous cannabinoids and the cannabinoid
receptor system has demonstrated a scientific basis for the efficacy
of synthetic and phytocannabinoids in pain management based on
serotonergic, dopaminergic, Substance P, and glutamatergic mechanisms,
interactions with the endogenous opioid system, as well as antioxidant
and anti-inflammatory effects. These mechanisms have been demonstrated
in both central and peripheral systems. Adjunctive effects of cannabis
and cannabinoids on depression, anxiety, spasticity, tremor, nausea
and anorexia also contribute to treatment benefits in chronic pain
patients. Whole cannabis and its extracts provide an entourage of
cannabinoids, terpenoids, and flavonoids that combine to create a
synergy of benefits in holistic treatment of chronic and intractable
pain.

Systematic examination of the toxicology and side effect profile of
cannabis and cannabinoids on long-term cognitive, other nervous
system, endocrine, hematological, and immunological function
demonstrate little documentation of significant detrimental effects,
and suggest a safety margin well within that of most prescription
medicines. The sole area of demonstrable concern surrounds chronic
pulmonary issues attendant with smoked cannabis. These problems are
possibly avoidable with harm reduction techniques such as
vaporization, and are totally so with alternative delivery methods
such as sublingual or nebulized cannabis-based medicine extracts.
Fears of cannabis-induced psychosis, addiction, and cognitive
impairment and deterioration have been largely exaggerated.

Oral synthetic THC (Marinol), a synthetically derived THC dissolved in
sesame oil, was developed by Unimed Pharmaceuticals. It is available
in capsules of 2.5, 5 and 10 mg and is marketed in the USA, Canada,
Australia, and some areas in Europe, and has proven quite
disappointing as a pain management tool. Cannabis proper, and a
variety of synthetic agents are in various stages of clinical
investigation. Development and FDA approval of synthetic cannabinoids
will require many years. In contrast, cannabis-based medicine extracts
have proven safe and effective in a large variety of pain conditions,
and are expected to attain governmental regulatory approval in the UK,
Western Europe and Canada within a very short time.

The History of Cannabis in Pain Management

Traditional knowledge of cannabis in China may span 5000 years, dating
to the legendary emperor, Shen-Nung. Julien (1849) wrote of the
physician Hoa-tho in the early 2nd century and his use of a cannabis
extract in anesthesia for major surgical procedures.

The Atharva Veda of India (dating to between 1400 and 2000 BCE)
mentions a sacred grass for anxiety, bhang, which remains a modern
term for cannabis. Medical references to cannabis date to Susruta in
the sixth to seventh centuries BCE. Dwarakanath (1965), described a
series of Ayurvedic and Arabic traditional preparations containing the
herb indicated for migraine, neuralgic and visceral pains.

Similar proof of the medicinal use of cannabis exists in records and
artifacts from ancient Egypt, Assyria, Israel/Palestine/Judea, and the
Greek and Roman Empires.

In common use throughout the Medieval world and Renaissance Europe,
the medical use of cannabis, or "Indian hemp" was reintroduced to the
West by O'Shaughnessy (1838-1840). His treatise on the subject dealt
with the apparent utility of a plant extract administered to patients
suffering from rabies, cholera, tetanus, infantile convulsions, but
also a series of painful rheumatological conditions. Of particular
note, even patients that succumbed to their illnesses were greatly
relieved by cannabis with convincing palliative benefits.

Shortly thereafter in England, Clendinning (1843) described his
results of treatment of 18 patients: 3 with headaches, one with
abdominal pain secondary to tumor, one with pain secondary to a
laceration, two with rheumatic joint pain, and one with gout. In each
case, the tincture of Indian hemp provided relief, even in cases of
morphine withdrawal symptoms.

In Ireland, Donovan (1845) extensively described his own extensive
trials with small doses of cannabis resin, mainly in patients with
various types of neuropathic and musculoskeletal pain. Effects were
almost uniformly impressive, with few side effects. He also described
the benefits of local application of hemp leaf oil on hemorrhoids and
neuralgic pains.

Over the next decades, numerous authorities recognized cannabis as
helpful for painful conditions. Sir John Russell Reynolds was
eventually to become Queen Victoria's personal physician. He
successfully treated her dysmenorrhea with a cannabis extract
throughout her adult life (Reynolds 1868) and used it extensively to
treat migraine and neuropathic pain.

Hobart Hare (1887): I have found the efficient dose of a pure extract
of hemp to be as powerful in relieving pain as the corresponding dose
of the same preparation of opium... During the time that this
remarkable drug is relieving pain a very curious psychical condition
sometimes manifests itself; namely, that the diminution of the pain
seems to be due to its fading away in the distance, so that the pain
becomes less and less, just as the pain in a delicate ear would grow
less and less as a beaten drum was carried farther and farther out of
the range of hearing.

In the French literature, See (1890) submitted a detailed report on
use of cannabis in the treatment of various disorders producing
gastric and intestinal pain, and found it preferable in efficacy and
side effects to opiates and bismuth.

Suckling (1891) noted the ability of cannabis to allow migraine
sufferers to return to work.

An American drug handbook stated the following: (Lilly, 1898)
"Antispasmodic, analgesic, anesthetic, narcotic, aphrodisiac.
Specially recommended in spasmodic and painful affections."

Hare (1922) still advocated use of cannabis noting "For the relief of
pain, particularly that depending on nerve disturbance, hemp is very
valuable."

An editor of the Journal of the American Medical Association, as late
as 1930 noted the ability of cannabis to achieve a labor with pain
burden substantially reduced or eliminated, followed by a tranquil
sleep (Anonymous 1930) without sequelae.

Despite its political disenfranchisement, Fishbein (1942) still
advocated oral preparations of cannabis in treatment of menstrual
(catamenial) migraine.

Cannabis remained in the British armamentarium somewhat longer, and
was extolled above opiates and barbiturates in the treatment of the
pain of hospitalized patients with duodenal ulcers (Douthwaite, 1947).

In Tashkent in the 1930's, cannabis or nasha was employed medicinally, despite Soviet prohibition (Benet 1975) for headache and pain of defloration. In Southeast Asia, cannabis remains useful (Martin 1975). Everywhere it is considered to be of analgesic value, comparable to the opium derivatives. Moreover, it can be added to any relaxant to reinforce its action. Cooked leaves, which have been dried in the sun, are used in quantities of several grams per bowl of water. This decoction helps especially to combat migraines and stiffness.

In a book about medicinal plants of India (Dastur, 1962) Charas [hashish] --- is a valuable narcotic, especially in cases where opium cannot be administered; it is of great value in malarial and periodical headaches, migraine, acute mania, whooping cough, cough of phthisis, asthma, anaemia of brain, nervous vomiting, tetanus, convulsion, insanity, delirium, dysuria, and nervous exhaustion; it is also used as an anaesthetic in dysmenorrhea, as an appetizer and aphrodisiac, as an anodyne in itching of eczema, neuralgia, severe pains of various kinds of corns, etc.

In Colombia the analgesic effects of a cannabis tincture were lauded (Partridge 1975) "the knowledge that cannabis can be used for treatment of pain is widespread." Rubin documented extensive usage of cannabis in Jamaica for a variety of conditions (Rubin, 1976; Rubin and Comitas, 1972), including headache.

In Brazil, Hutchinson (1975) "Such an infusion [of leaves] is taken to relieve rheumatism, "female troubles", colic and other common complaints. For toothache, marijuana is frequently packed into and around the aching tooth and left for a period of time, during which it supposedly performs an analgesic function".

Cannabis and Cannabinoids as Medicine.

Cannabis Proper Cannabis is traditionally employed therapeutically by smoking or ingestion. Grotenhermen has produced an excellent summary of "Practical Hints" (Grotenhermen, 2002), as have Brazis and Matthre (1997) and Russo (2002).

Dosing of therapeutic cannabis must be titrated to the patient's need. In general, 5 mg of THC content represents a threshold dose for noticeable effects in the average adult (Grotenhermen 2002). Whereas tolerance to cardiovascular effects (tachycardia) and psychoactive effects ("high") are achieved after some days to weeks of chronic usage, observed clinical and "anecdotal" reports support retention of analgesic efficacy over the long term. Occasionally, upwards dose titration is necessary, as is true for any agent.

Allergies to cannabis are rare, although some may experience rhinitis symptoms, particularly when exposed to the smoke of the unrefined product. People employing cannabis therapeutically must be warned of the usual caveats assigned to any potentially sedative drug: due care with operation of machinery, motor vehicles, etc., which are analogous to the industry warnings for Marinol® (synthetic THC).

Acute over-dosages of cannabis are self-limited, and most frequently consist of panic reactions. These are uniquely sensitive to reassurance ("talking down") and are quite unusual once a patient becomes familiar with the drug. Cannabis has a unique distinction of safety over four millennia of analgesic usage: No deaths due to direct toxicity of cannabis have ever been documented in the medical literature.

Some cannabis-drug interactions are apparent, but are few in number. Additive sedative effects with other agents, including alcohol, may be observed. Similarly however, additive or synergistic anti-emetic and analgesic benefits may accrue when combining dopamine agonist neuroleptics and cannabis (Carta, Gessa, and Nava 1999). Cannabis may accelerate metabolism of theophylline, while slowing that of barbiturates. Anticholinergic-induced tachycardia may be accentuated by cannabis, while this effect is countered by beta-blockers (Grotenhermen 2002). Indomethacin seems to reduce slightly the psychoactive and tachycardic effects of cannabis (Perez-Reyes et al. 1991). As discussed above, synergistic analgesic benefits may accrue with concomitant usage of cannabis and opioids (Cichewicz et al. 1999; Hare 1887). CBD is a powerful inhibitor of cytochrome P450 isozymes 3A4, 2C19, and 2D6 (Bornheim et al. 1994; Bornheim and Grillo 1998) indicating the need for caution in cannabis patients taking that component in conjunction with fentanyl, sildenafil (Viagra®), tricyclic antidepressants and anti-arrhythmic drugs.

Crude cannabis contains most of its THC in the form of delta-9-THC acids that must be decarboxylated by heating to be activated. This occurs automatically when cannabis is smoked, whereas cannabis that is employed orally should be heated to 200-210šC. for 5 minutes prior to ingestion (Brenneisen 1984).

Contrary to disseminated propaganda in the USA, average cannabis potency has varied little over the last 3 decades (ElSohly et al. 2000; Mikuriya and Aldrich 1988). It is true that the maximum potency has increased through applied genetics, cultivation and harvesting techniques. This goal is achieved through production of clonal cultivation of the preferred female plants and maximization of the yield of unsterilized flowering tops known as sinsemilla (Spanish for "without seed"). In this manner a concentration of glandular trichomes where THC and therapeutic terpenoids are produced is effected. Resultant yields of THC may exceed 20% by weight. This is potentially advantageous, particularly when smoked, because a therapeutic dosage of THC is obtained with fewer inhalations, thereby decreasing lung exposure to tars and carcinogens. As noted by Professor Wayne Hall (Lords 1998).

Indeed, it is conceivable that increased potency may have little or no adverse effect if users are able to titrate their dose to achieve the desired state of intoxication. If users do titrate their dose, the use of more potent cannabis products would reduce the amount of cannabis material that was smoked, thereby marginally reducing the respiratory risks of cannabis smoking.

A considerable concentration of THC, other cannabinoids and terpenoids may also be achieved through some simple processing of crude dried cannabis. Techniques for sieving or washing of cannabis to isolate the trichomes to produce hashish are well described (Clarke 1998; Rosenthal, Gieringer, and Mikuriya 1997), and may produce potential yields of 40-60% THC. Clarke demonstrates a simple method of rolling the resultant powdery material into a joint of pure hashish, termed "smoking the snake" (Clarke 1998), providing a relatively pure product for inhalation.

Cultivation techniques are beyond the scope of this review, but emphasis should focus on potent medicinal strains, scrupulous organic cultivation of female plants, clonal selection and augmentation, and appropriate processing with a high degree of quality control throughout the process. It deserves emphasis that clinical cannabis patients benefit from consistent quality and dosing. This is extremely difficult to achieve on a practical basis, unless cloned cannabis strains or standardized extracts are employed. Additionally, although cannabis is often touted as relatively "pest-free," it is subject to predation by a number of insects, bacteria, viruses, fungi, etc. (McPartland, Clarke and Watson 2000).

Cannabis strains in the USA are THC predominant, almost uniformly devoid of CBD content (Gieringer 1999). While this may be appropriate for certain medical conditions, patients with concomitant muscle spasm, anxiety, seizure disorders, or susceptibility to psychoactive effects may not achieve optimal results.

The labor required to manage cannabis genetics, culture, maintenance of "organic" technique without contamination, processing and quality control are likely beyond the ken and capabilities of most patients, particularly those with chronic pain.

It remains the case that smoked cannabis is a crude delivery system with some inherent respiratory risk. This fact, taken with the inability to develop smoked cannabis into an FDA-approved medicine in the USA, makes the development of alternative rapid-delivery cannabis-based systems mandatory.

Oral Use of Cannabis

A variety of issues attend oral cannabis administration. The most
important concerns bioavailability. Oral absorption of cannabinoids is
slow and erratic at best, often requiring 30-120 minutes. In HIV
positive or chemotherapy patients and in acute migraine, nausea and
emesis may preclude oral usage altogether. Additionally, oral THC is
subject to the "first pass effect" of hepatic metabolism yielding
11-hydroxy-THC, considerably more psychoactive than THC itself. Thus,
some patients become 3too high2 even on low doses of medicine, such as
2.5 mg of THC as dronabinol.

Advantages of oral usage are its avoidance of lung exposure in those
who are immunosuppressed or have impaired pulmonary function, and its
prolonged half-life. This may be of advantage for nocturnal complaints
where sedation is less of an issue.

Grotenhermen suggests dose titration beginning with the equivalent of
2.5 mg of oral THC bid with increases as needed and tolerated
(Grotenhermen 2002). Most painful clinical conditions require tid
dosing of cannabis.

THC, CBD and terpenoids are all highly lipophilic. Gastrointestinal
absorption is markedly enhanced by inclusion of lipids in the cooked
preparations. Therapeutic tincture extraction in alcohol is also possible.

Smoked Cannabis

Techniques of smoking cannabis are legion. Pharmacodynamically,
smoking would be an ideal method of application of clinical cannabis,
but for the attendant pulmonary issues. Clinical effects are noted
within seconds to minutes after smoking. Inhalation avoids the first
pass effect that hampers oral use, and allows effective dosage
titration. When symptoms return, repeat dosage is achieved quickly and
easily. Overdosage is frequently avoidable.

Traditional smoking techniques in the USA make prolonged holding of a
marijuana "toke" de rigueur. From a dose-response standpoint, this is
unnecessary. Inhaled THC is well absorbed after a very brief interval,
and subjective high and serum THC levels do not increase beyond a
maximum 10-second inhalation. Furthermore, prolonged breath holding
under pressure increases the potential for hypoxia or
pneumothorax.

Contamination of herbal cannabis by pesticides, herbicides, and
bacterial or fungal agents is possible, and may represent a threat to
the smoker, especially immunosuppressed patients. Scrupulous
cultivation techniques avoid some of these issues. McPartland
recommends pasteurization of herbal cannabis by heating in an oven of
150C. for 5 minutes (McPartland 2001).

Waterpipes and bongs are popular techniques for cooling smoke. While
they may reduce particulate matter as well, THC content and
pharmaceutical efficiency also seem to be compromised. Surprisingly,
the unfiltered "joint" seems to represent the most efficient means for
conventional smoking, although use of hashish in a pipe (without
tobacco) was not examined.

Vaporizers for Cannabis Administration

Vaporization of herbal cannabis may allow delivery of THC and
terpenoid components below the flash point of the leaf, thereby
reducing exposure to smoke, tar and carcinogens. The technology has
been hampered in its development by paraphernalia laws. Initial
investigations of available devices had disappointing results, but
further studies have demonstrated promising benefits on avoidance of
carcinogenic components from smoking (Gieringer 2001). Research continues.

Sublingual Tincture of Cannabis

This method of administration is under investigation by GW
Pharmaceuticals in the United Kingdom employing combinations of
specific strains of cannabis that are rich in THC or CBD. Terpenoids
and other minor components that are important to therapeutic effects
of cannabis are retained. Dose-metered sublingual sprays are currently
in Phase 2 and 3 clinical trials for a variety of indications. Initial
results indicate good bioavailability and excellent patient tolerance
and clinical effects. Painful conditions have been of particular note
in this research.

Aerosol THC Preparations

Cannabis has a long history of use in asthma, even as a smoked
preparation. A pure THC aerosol has been attempted numerous times in
the past. Physical and delivery issues have been challenging, but more
interestingly, pure THC seems to have an irritating and even
bronchoconstrictive effect when employed in isolation (Tashkin et al.
1977). Some authors believe that anti-inflammatory effects of
concomitant terpenoid and flavonoid administration are necessary for
full effects and tolerance in pursuit of the pulmonary route. Further
research is underway by GW Pharmaceuticals, Inhale Therapeutic
Systems, and possibly others.

Marinol (dronabinol, synthetic THC)

Marinol is a synthetically derived THC dissolved in sesame oil,
developed by Unimed Pharmaceuticals. It is available in capsules of
2.5, 5 and 10 mg and is marketed in the USA, Canada, Australia, and
some areas in Europe. Until 1999, Marinol was a Schedule II drug in
the USA with close scrutiny to its usage, which was restricted to
indications of AIDS-associated anorexia and cancer chemotherapy. After
safety studies revealed a low potential for abuse or diversion,
dronabinol was "down-scheduled" to Schedule III in 1999, allowing
refill prescriptions for up to 6 months, and its "off-label"
administration for any indication. Clinicians have utilized Marinol to
only a limited degree. Its bioavailability is only 25-30% of an
equivalent smoked dose of THC (Association 1997). Additional problems
include the first pass effect of hepatic metabolism, which results in
the production of a more psychoactive metabolite 11-hydroxy-THC, and
its considerable cost, which may exceed US $600 per month for the
lowest dosage of 2.5 mg tid. Considerable anecdotal data supports
preference by patients of smoked cannabis over dronabinol.

Nabilone

Nabilone is a synthetic cannabinoid said to be pharmacologically
similar to THC, but more potent, less apt to produce euphoria, and
possessing lower "abuse potential" (Association 1997). It is produced
by Eli Lilly Company as Cesamet and is available in the UK, Canada,
Australia and certain countries in Europe as an agent for nausea in
chemotherapy. Some scattered reports have noted benefit on spasticity
in MS, and effects on dyskinesias.

A group in the UK assessed analgesic effects of nabilone in patients
including some with neuropathic pain (Notcutt, Price, and Chapman
1997). Side effects of drowsiness and dysphoria were troubling.
Several patients claimed improved pain relief and fewer side effects
with smoked cannabis and preferred it to this legal alternative.
Nabilone's cost was also estimated to be 10 times higher than cannabis
even at black market rates.

Future Directions and Needs

Future directions for research on cannabis and cannabinoids will be
primarily determined by political factors. Studies with smoked
cannabis in the USA will continue under constraints imposed by NIDA:
limited access to low potency smoked marijuana with rigorous
oversight. Such studies may have limited applicability to the actual
potential of true medical-grade cannabis or cannabis-based medicine
extracts.

Herbal cannabis as a smoked medicine will never fulfill FDA guidelines
to become a prescription medicine. Such a process requires absolute
standardization of constituents, rigorous quality control,
bacteriological purity, safety, reliability, reproducibility, and
uniform dose titration. In contrast cannabis-based medicine extracts,
whether employed sublingually or via aerosol, can easily meet this
burden and will likely achieve market approval in Europe and Canada
within months.

[sidebar]

DR. RUSSO'S FINDINGS AND POLICY RECOMMENDATIONS

1) Cannabis has a long and documented history in the treatment of
neuropathic, musculoskeletal, spasmodic, and inflammatory pain
conditions. Cannabis has a historical role as a palliative agent in
terminal patients

2) Additional adjunctive antidepressant and anti-anxiety properties of
cannabis, as well as its anti-spasticity, and appetite stimulatory
effects offer important therapeutic value in pain management patients.

3) Modern pharmacological and receptor studies of cannabis and
cannabinoids support therapeutic claims.

4) Cannabinoids represent an important parallel system to the
endogenous opioid system of pain modulation, and administration of
cannabinoids can effectively synergize opioid responses while
mitigating side effects. Cannabinoids show unique promise in treatment
of neuropathic pain.

5) Historically, governmental commissions have almost uniformly
recommended allowance or provision of cannabis for medical indications
including pain.

6) Financial investment in research into cannabis and cannabinoid
strategies for pain management are deserving of support by medical and
governmental organizations.

7) Current research supports the contention that no single agent will
ever possess the spectrum of synergistic activity of whole cannabis.

8) Alternative delivery systems for whole cannabis and especially its
standardized extracts represent the logical methods for administering
this medicine to pain patients.

9) These practical and effective methods of cannabis administration
(sublingual and inhaled CBME) in painful conditions are available now
in other countries with imminent licensure. Government agencies should
expedite efforts to provide comparable access to rapid onset
alternative methods of delivery of standardized cannabis-based
medicine extracts to deserving patients, or, alternatively until their
approval, re-open the Compassionate Use IND, with the availability of
potent, well manicured sterilized cannabis. I believe that the USA
should provide expedited access to cannabis-based medicine extracts
and appropriate synthetic cannabinoids by patients with pain
conditions, or, re-open the Compassionate Use Investigational New Drug
(IND) program to provide potent, well-manicured medicinal-grade
cannabis to chronic pain patients.