Chronic Pain, Opioid Dependence and Medical

Marijuana

Juan Sanchez-Ramos, PhD, MDProfessor of Neurology

University of South Florida

Pain

• Pain is most common reason for physician consultation in the US– It is major symptom in many medical conditions

• Definition is based on subjective experience– Pain is an unpleasant sensory and emotional

experience associated with actual or potential tissue damage

– Acute pain is transitory, lasting only until the noxious stimulus is removed or the underlying damage or pathology has healed.

Chronic Pain

• Definition: pain that “persists beyond the normal tissue healing time, which is assumed to be 3 months”– From the American Pain Society and the International

Association for the Study of Pain• Prevalence: 1/3 of the adult population in US meets

this definition of chronic pain• Common conditions associated with chronic pain:

cancer (and its treatment), degenerative spine disease, osteoarthritis, fibromyalgia, human immunodeficiency virus, migraine, diabetic neuropathy, and postherpetic neuralgia

Consequences of Chronic Pain

• Impact on mood and mental health– Prevalence of psychopathology ranges 33-46% in

chronic pain conditions– Disturbance of sleep in 50-89% in chronic pain

population– Increased rate major depression, suicidal ideation,

suicide attempts• Effects on cognition, brain function– Decline memory, attention in 2/3 of patients with

chronic pain syndromes

Consequences of Chronic Pain

• Impact on cardiovascular health– Intensity of chronic pain was a significant

predictor of hypertension, (independent of age, sex race and FH).

• Impact on sexual function – 54-63% of patients have sexual dysfunction

• Impact on quality of life– Interference with social life, work and daily

activities

Treatment of Pain with Opioids

• If opioids are considered, start with short-term or intermittent opioid use for severe pain flare-ups as an alternative to sustained opioid use.

• Long-term use of opioids for chronic pain is not an evidence-based therapy

• Avoid dose escalation to levels where discontinuation becomes difficult and risks of adverse events are increased.

Impact of opioid Rx in US

• Even though significant pain goes undertreated, the US is experiencing a significant public health threat from overdose deaths involving prescription opioids

• fatal poisonings involving opioid analgesics tripled from 4,000 to 13,800 from 1999 through 2006 (National Center for Health Statistics)

Increase in US overdose deaths related toopioids and unidentified drugs, 1999–2007

Mortality Data—Vital Statistics NCHS’s Multiple Cause of Death Data, 1959–2006. National Bureau of Economic Research. Available at: http:www.nber. org/data/multicause.html

Deaths reported to poison centers per 10,000 single substance exposures (National Poison Database System (NPDS), which tracks all cases recorded from 61 regional poison centers

Total prescriptions dispensed in the US of Methadone, Hydrocodone and Oxycodone

Methadone represents less than 5% of total opioid prescriptions dispensed but a third of opioid-related deaths nationwide

Methadone and other opioid deaths in the US

Methadone accounts for 1/3 of opioid-related deaths in the US

Risk of death

• Increases with increasing opioid dose (up to 7 times the risk of regularly scheduled dose)

• Increases significantly in substance abusers treated for chronic pain, cancer and acute pain (by 2 and 3 times)

• Death risk increases significantly in males with chronic pain, cancer, acute pain and substance abuse

JAMA. 2011;305(13):1315-1321)

JAMA. 2011;305(13):1315-1321)

Factors that contribute to opioid-related deaths

• Physician errors: initiating methadone at too high dose, over-relying on published equianalgesic conversion tables, titrating doses too rapidly, lack of knowledge on unique pharmacokinetics of methadone, failing to monitor patients at risk for substance misuse, overestimating tolerance to respiratory depresson conferred by prior opioid use in patients with chronic pain

• Patient non-adherence to Medication Regimen: escalating doses without prescriber knowledge or mixing opioids with alcohol, benzodiazepines, or other substances.

• Payer policies that mandate methadone as 1st line therapy: methadone less expensive than many opioids

Factors that contribute to opioid-related deaths

• Unexpected mental-health co-morbidities : mental disorders, and substance use disorders have been correlated with chronic pain.– 59% of patients with chronic pain have depression– 64% anxiety– Drug abuse more likely in patient with depression

than patients without depression

Factors that contribute to opioid-related deaths

• Presence of additional CNS depressant drugs (alcohol, benzodiazepines and anti-depressants)– Alcohol is found more frequently in opiate deaths

than any other substance– In 2006, about half of all US opioid-related deaths

involved more than one type of drug with benzodiazepines mentioned in 17% of the deaths

– Multiple substances were evident in almost 80% of opioid-associated deaths from 1999 to 2004 in West Virginia

Factors that contribute to opioid-related deaths

Cannabis for Pain

• Pain has been treated with preparations of cannabis for centuries.

• There is a resurgence of scientific interest in the cannabinoids and their medical application for a wide-range of health disorders.

• A review of the recent medical literature on cannabis and pain has revealed many well-conducted clinical studies that support its efficacy as an analgesic

Smoked Cannabis Herb for Pain

• A cross-sectional analysis of 209 chronic non-cancer pain patients was conducted

• 15 percent of patients reported using smoked cannabis to treat pain.

• The authors reported improvements in pain, mood, and sleep, and stated side effects were primarily dry mouth and euphoria. (Buggy et al., 2003)

Cross-sectional analysis

Smoked Cannabis for Neuropathic Pain

• A clinical study on smoked cannabis evaluated its effect on neuropathic pain attributed to HIV.

• The study utilized a double-blind placebo controlled design. Fifty patients smoked either 3.56 percent THC cannabis cigarettes or placebo cigarettes three times a day for five days.

• Smoked cannabis significantly reduced pain by 34 percent, compared to 17 percent with placebo.

• Side effects were mild and included sedation and anxiety. (Abrams et al., 2007)

double-blind placebo controlled design

Effects of smoked cannabis on neuropathic pain in HIV

• This was a phase II, double-blind, placebo-controlled, crossover trial of analgesia with smoked cannabis in HIV-associated distal sensory predominant polyneuropathy (DSPN). Smoked cannabis was generally well tolerated and effective when added to concomitant analgesic therapy in patients with medically refractory pain due to HIV DSPN. (Ellis et al., 2009)

• Of 127 volunteers screened, 34 eligible subjects enrolled and 28 completed both cannabis and placebo treatments.

• Among the completers, pain relief was greater with cannabis than placebo

• The proportions of subjects achieving at least 30% pain relief with cannabis versus placebo were 0.46 (95%CI 0.28, 0.65) and 0.18 (0.03, 0.32).

• Mood and daily functioning improved to a similar extent during both treatment periods. (Ellis et al., 2009)

Effects of smoked cannabis on neuropathic pain in HIV (cont’d)

Effects of smoked cannabis on neuropathic pain in HIV (cont’d)

• Eligible subjects had neuropathic pain refractory to at least two previous analgesic classes;

• they continued on their pre-study analgesic regimens throughout the trial. Regulatory considerations dictated that subjects smoke under direct observation in a hospital setting.

• Treatments were placebo and active cannabis ranging in potency between 1 and 8% Δ9THC, four times daily for 5 consecutive days during each of 2 treatment weeks, separated by a 2-week washout.

Smoked Cannabis for chronic neuropathic pain

• Adults with post-traumatic or postsurgical neuropathic pain were randomly assigned to receive cannabis at four potencies (0%, 2.5%, 6% and 9.4% tetrahydrocannabinol) over four 14-day periods in a crossover trial.

• Participants inhaled a single 25-mg dose through a pipe three times daily for the first five days in each cycle, followed by a nine-day washout period. Daily average pain intensity was measured using an 11-point numeric rating scale. We recorded effects on mood, sleep and quality of life, as well as adverse events.

• 23 participants (mean age 45.4) were enrolled 21 completed the trial.

• The average daily pain intensity, measured on the 11-point numeric rating scale, was signficantly improved with the highest concentration 9.4% THC compared to placebo.

• Participants receiving 9.4% THC reported improved ability to fall asleep and improved quality of sleep (Ware et al., 2010)

Smoked Cannabis for chronic neuropathic pain (cont’d)

Double-blind, placebo-control

Case-Series: Marijuana Rx at a Pain Center

• A case-series study of thirty patients who use medical marijuana at a pain center in Canada found that 93 percent of patients reported moderate or greater pain relief.

• Side effects were reported by 76 percent of patients; they included increased appetite, weight gain, and slowed thoughts (Lynch et al., 2006)

Sativex (extract from cannabis plant) for pain refractory to opioid Rx

• Twenty-four patients with multiple sclerosis (18) spinal cord injury (4), brachial plexus damage (1), and limb amputation due to neurofibromatosis were given cannabis extracts by oral-mucosal spray (Sativex).

• Cannabis medicinal extracts improved neurogenic symptoms unresponsive to standard treatments.

• Unwanted effects are predictable and generally well tolerated. Larger scale studies are warranted to confirm these findings. (Wade et al. 2003)

Double-blind, placebo-control study

Sativex (THC:CBD) alleviates pain refractory to opioid Rx

• A preparation of cannabis extracts of THC:CBD (Sativex) an oral-mucosal spray, was studied in individuals with intractable pain associated with nerve root avulsions not alleviated by conventional analgesic therapy.

• The study was conducted using a double-blind placebo-controlled design.

• The active medication did not attain the primary endpoint, a pre-designated decrease by two points in the pain severity scale in the last 7 days of the study. However, the medication improved measures of pain in a statistically significant manner. In addition, measures of sleep were significantly improved.

double-blind placebo-controlled design

(Berman et al., 2004)

Sativex for Cancer Pain

• A total 177 patients with cancer pain, who experienced inadequate analgesia despite chronic opioid dosing, entered a two-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial.

• The cannabis preparation, Sativex (THC:CBD) delivered via an oral mucosal spray was efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids and was well tolerated. (Johnson et al, 2010)

Synthetic cannabinoidalleviates acute pain

• A synthetic cannabinoid, levonantradol, was compared to placebo on fifty-six patients with acute pain.

• Four different intramuscular injections (doses of 1.5, 2, 2.5, and 3 mg) all provided significant analgesia

• Side effects were mild, with drowsiness being the most frequent. Jain et al., 1981

Double-blind, placebo-control study

Oral Δ9THC at single dose not effective for post-op pain

• The effect of oral THC on postoperative pain was evaluated on forty women after hysterectomy.

• On the second day after surgery, the patients were given either 5 mg oral THC or placebo.

• No statistically significant analgesic effect was reported, and side effects were minimal (Buggy et al., 2003)

Double-blind, placebo-control study

Risk of Death with Cannabis Use• Systematic peer-reviewed literature searches were

conducted in Medline, EMBASE and PsycINFO to identify data on mortality associated with cannabis use. Searches were limited to humans and time frame January 1990 to January 2008.

• Reference lists of review articles and of specific studies deemed important by colleagues were searched to identify additional studies.

• Key Findings: There was insufficient evidence, due to low number of studies, to assess whether the all-cause mortality rate is elevated among cannabis users in the general population. (Calabria et al, 2010)

Risk of Death (cont’d)

• Case–control studies suggest that some adverse health outcomes may be elevated among heavy cannabis users, namely, fatal motor vehicle accidents, and possibly respiratory and brain cancers.

• Conclusions. There is a need for long-term cohort studies that follow cannabis using individuals into old age, when the likelihood of any detrimental effects of cannabis use are more likely to emerge among those who persist in using cannabis into middle age and older. (Calabria et al, 2010)

DRUG CLASSIFICATION SpecificDrugs perCategory

PrimarySuspect of the

Death

Secondary Suspect(Contributing to

death)

Total Deaths Reported1/1/97 - 6/30/05

A. MARIJUANAalso known as: Cannabis sativa L

MarijuanaCannabis

Cannabinoids

0 279 279

B. ANTI-EMETICS(used to treat vomiting)

CompazineReglanMarinolZofranAnzemetKytrilTigan

196 429 625

C. ANTI-SPASMODICS(used to treat muscle spasms)

BaclofenZanaflex

118 56 174

D. ANTI-PSYCHOTICS(used to treat psychosis)

HaldolLithiumNeurontin

1,593 702 2,295

E. OTHER POPULAR DRUGS(used to treat various conditions including ADD, depression, narcolepsy, erectile dysfunction, and pain)

RitalinWellbutrinAdderallViagraVioxx*

8,101 492 8,593

F. TOTALS of A-ENumberof Drugsin Total

PrimarySuspect of the

Death

Secondary Suspect(Contributing to

death)

Total Deaths Reported1/1/97 - 6/30/05

TOTAL DEATHS FROM MARIJUANA 1 0 279 279

TOTAL DEATHS FROM 17 FDA-APPROVED DRUGS

17 10,008 1,679 11,687

Summary of Deaths based on Drug Classification (data obtained from FDA)Comparison with 17 other approved drugs

Can Marijuana Cause Death?• YES: Thomas Geller, MD, wrote the following in the article

titled "Cerebellar Infarction in Adolescent Males Associated with Acute Marijuana Use, (Pediatrics, 2004)– "Each of the 3 cannabis-associated cases of cerebellar infarction was

confirmed by biopsy (1 case) or necropsy (2 cases)... Brainstem compromise caused by cerebellar and cerebral edema led to death in the 2 fatal cases.“

• YES: Liliana Bachs, MD, wrote the following the article titled "Acute Cardiovascular Fatalities Following Cannabis Use," published in the journal Forensic Science International (2001):– "Cannabis is generally considered to be a drug with very low toxicity. In this

paper, we report six cases where recent cannabis intake was associated with sudden and unexpected death. An acute cardiovascular event was the probable cause of death. In all cases, cannabis intake was documented by blood analysis... Further investigation of clinical, toxicologial and epidemiological aspects are needed to enlighten causality between cannabis intake and acute cardiovascular events."

Can Marijuana Cause Death??

• NOT SURE: Liliana Bachs, MD, Senior Medical Officer at the Norwegian Institute of Public Health, wrote in a Nov. 28, 2005 email to ProCon.org:– "Causality is a difficult assessment in forensic toxicology. It

is often an 'exclusion diagnosis,' and so it is in our cases. I'm therefore not sure about how to classify those deaths. ”

• NO: Joycelyn Elders, MD, former US Surgeon General, wrote in a Mar. 26, 2004 editorial published in the Providence Journal:– "Unlike many of the drugs we prescribe every day,

marijuana has never been proven to cause a fatal overdose."

DON’T KNOW: The Substance Abuse and Mental Health Services Administration's (SAMHSA) 2003 report Mortality Data from the Drug Abuse Warning Network, 2001 stated:"Marijuana is rarely the only drug involved in a drug abuse death. Thus ... The proportion of marijuana-induced cases labeled as 'One drug' (i.e., marijuana only) will be zero or nearly zero.“ 2003 - Substance Abuse and Mental Health Services Administration

More Expert Opinions on the question, Has Marijuana Caused Death?

NO: Stephen Sidney, MD, Associate Director for Clinical Research at Kaiser Permanente, wrote the following in the article titled "Comparing Cannabis with Tobacco -- Again," published in the British Medical Journal (2004): "No acute lethal overdoses of cannabis are known, in contrast to several of its illegal (for example, cocaine) and legal (for example, alcohol, aspirin, acetaminophen) counterparts...Although the use of cannabis is not harmless, the current knowledge base does not support the assertion that it has any notable adverse public health impact in relation to mortality.“

NO: Joycelyn Elders, MD, former US Surgeon General, wrote the following in her Mar. 26, 2004 editorial published in the Providence Journal:"Unlike many of the drugs we prescribe every day, marijuana has never been proven to cause a fatal overdose."

Can Marijuana Cause Death?

• NO: The U.S. Office of Applied Studies, Substance Abuse and Mental Health Services Administration (SAMHSA) published a July 2001 report from the Drug Abuse Warning Network (DAWN), Mortality Data From Dawn:– "Marijuana is rarely the only drug involved in a drug

abuse death. Thus, in most cases, the proportion of marijuana-involved cases labeled as ‘One drug’ (i.e., marijuana only) will be zero or nearly zero."

Conclusions

• Opioids for treatment of chronic pain carry a significantly increased morbidity and mortality

• Cannabis preparations are useful for treatment of pain refractory to standard opioid therapy

• Risk of mortality from use of cannabis preparations is not increased compared to the risk of death from use of over-the-counter analgesics and prescription medications.