THC-Morphine Analgesic

[grammychronic]

SUMMARY
It is known from the folk medicine that Cannabis may reduce pain. The aim of the pain study
was to compare analgesic effects of oral delta-9-tetrahydrocannabinol (THC, dronabinol,
Marinol‚, main psychoactive component of the Cannabis plant) and a THC-morphine
combination to morphine and placebo. This pain study was performed with 12 healthy
volunteers in four different experimental models of acute pain. Additionally, side effects and vital
functions were monitored and blood samples collected for the pharmacokinetic profiling of oral
THC. In none of the pain models THC showed a significant analgesic effect. The THC-morphine
combination showed a slight tendency to an additive effect compared to morphine alone, but
this was not statistically significant. The side effects observed with THC were mainly sleepiness
and mild to intermediate psychotropic side effects. The plasma concentrations of THC, analysed
with gas chromatography mass-spectrometry, were very low, showed a plasma peak time of 60
to 120 min with high inter-individual variation. In addition, an extensive liver first pass
metabolism could be observed leading to high metabolite-THC ratios.
In the second part of the present work the aim was to develop an application form as
alternative to the Marinol‚ capsules. The very lipophilic THC was solubilised with
Cremophor‚ RH 40 leading to a water-soluble THC formulation, which could be used as
inhalation solution for the pulmonal administration of THC. This formulation underwent an in
vitro quality assurance focussing on stability and physiological tolerability. Additionally, the
particle size of the droplets in the aerosol and the output rate of the evaluated nebuliser system
for the clinical application were determined.
In the third part of this work, the developed application form (inhalation solution) was used for
a second clinical study with eight healthy volunteers. The pharmacokinetic properties of
pulmonal THC were compared to intravenous THC and the analgesic effects were determined
comparing with pulmonal placebo. With the pulmonal application form the very low
bioavailability of oral THC could be increased up to 6-fold. Comparing the elimination half-lives,
a 5-fold decrease of the half-life after pulmonal and intravenous THC compared to oral THC
was observed, indicating that absorption is the time-determining step in the pharmacokinetic
behaviour of orally administered THC. This was also reflected by the peak plasma concentration
time, which occurred right at the end of the inhalation procedure of about 20 min (3 to 6-times
earlier than with oral THC). Peak plasma concentrations were much higher after pulmonal than
oral administration causing much less side effects, indicating that not only THC itself is
responsible for the psychotropic side effects but also the known strongly psychoactive
Summary ii
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11-hydroxy-THC. Metabolite-THC ratios were found to be much lower after pulmonal and
intravenous THC than after oral THC.
The most prominent side effect of pulmonal THC was the irritation of the throat and coughing
during the inhalation, which were reversible within short time after finishing the inhalation
procedure.
Despite the increased bioavailability of pulmonal THC no analgesic effect resulted,
suggesting that the bioavailability does not affect the efficacy in the pain reducing properties of
THC. We assume that the used experimental pain models, which were all models of acute pain,
were not appropriate to study the analgesic properties of THC. Further experiments are needed
to evaluate the appropriate pain tests for THC and healthy subjects. In addition, it would be very
interesting to investigate the analgesic effect of the pulmonal THC in patients suffering from
chronic and neuropathic pain.

Full Report Here
http://pages.unibas.ch/diss/2004/DabsB_6910.pdf

[Sequoiacrone]

The effects of smoked cannabis in painful peripheral neuropathy and cancer pain refractory to opiods.

Author(s)Abrams DI, Jay Ch, Petersen K, Shade S, Vizoso H, Reda H, Benowitz N, Rowbotham M.Journal, Volume, IssueIACM 2nd Conference on Cannabinoids in Medicine, Cologne, 12-13 September 2003, International Association for Cannabis as Medicine.

Major outcome(s)10 of the 16 participants experienced a greater than 30% reduction in their pain


INTRODUCTION: There is significant evidence that cannabinoids may be involved in the modulation of pain, especially of neuropathic origin. There is also theoretical rationale to suggest that cannabinoids may provide synergistic analgesia with opioids while possibly reducing opioid-related side effects. No information is available on potential pharmacokinetic interactions between cannabinoids and opioids.
METHODS: We are currently conducting two clinical trials of smoked marijuana in two populations of patients with pain: HIV patients with painful peripheral neuropathy and cancer patients with persistent pain despite an opioid analgesic. Both studies are designed to begin with a 16 patient open-label pilot proof-of-concept phase. If effectiveness is demonstrated in the pilot, the magnitude of the effect allows us to calculate a follow-on randomized, double-blind controlled trial of smoked marijuana vs smoked placebo. In addition to the effect of smoked marijuana on the subjects’ chronic clinical pain, we are also evaluating the impact on an experimental heat/capsaicin pain model. Here we report experience with the open label phase of the neuropathy study.
RESULTS: Sixteen subjects (14 men, 2 women, mean age 43 years) completed the HIV neuropathy pilot trial. Patients had an average of 6 years of neuropathic pain. In 3 cases the pain was felt to be secondary to HIV alone, in 8 secondary to dideoxynucleoside antiretrovirals and to both in 5. Excellent correlation was seen between the response to smoking in the effect on both the chronic neuropathic and the acute experimental pain model over a six-hour period. Overall 10 of the 16 participants experienced a greater than 30% reduction in their neuropathic pain after seven days. This allowed us to proceed with our currently enrolling randomized placebo-controlled trial with a target sample size of 50 subjects. Additional controlled trials of smoked marijuana for HIV peripheral neuropathy are being conducted by other University of California Center for Medicinal Cannabis Research investigators.
CONCLUSION: Preliminary results from a small, uncontrolled trial of smoked marijuana in HIV peripheral neuropathy are encouraging. The ongoing randomized trials will better elucidate the role of cannabinoids in this condition. A heat/capsaicin experimental pain model appears to be a good predictor of response to chronic pain. The potential of a beneficial clinical interaction between cannabinoids and opioids requires further study.

Source: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=96