Cannabis Versus Opioids For Pain

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Continuing Education Activity

Opioids are used to treat and manage chronic and severe pain, but they can potentially abuse and depend. This activity reviews the limitations, signs, and symptoms of adverse events and other critical elements of opioid therapy and cannabinoids in a patient with chronic pain related to the essential points needed by members of an interprofessional team managing the care of patients.


  • Describe limitations of the use of opioids and cannabinoids in a patient with chronic pain.
  • Explain signs and symptoms of opioids related drug abuse.
  • Identify legal issues related to the use of cannabis.
  • Review issues related to the use of opioids in patients with chronic pain.


In a human body, pain is an inbuilt alarm that goes off when there is potential or actual underlying damage to shift the person's attention towards the problem.[1][2][3] It is the most common reason an individual seeks medical assistance. Pain comprises different components, including nociception, perception of pain, suffering, and pain behaviors. Although an essential mechanism, it may become a nuisance if the pain persists for too long due to suffering and pain behavior. Chronic unrelenting pain can cause many psychological, physical, and emotional stress.[4] 

The search for an ideal medicine for pain relief has been in progress since ancient times, as there are no certain drugs for a few types of pain. Several strategies mitigate intractable pain refractory to therapy, with opioids being the mainstay in many pain management protocols, and recently, cannabinoids have shown some promise.[5][6]



Endogenous opioids are present physiologically in the body, which help in the modulation of pain by acting on presynaptic μ-, κ-, and δ-opioid receptors to reduce excitatory neurotransmitter release by decreasing calcium influx in the presynaptic membrane and increasing potassium influx in the postsynaptic membrane.[7][8] Pharmacologists use the exact characteristics of the opioid receptors to develop and administer exogenous opioids for pain management. These exogenous opioids have a dual mechanism of action; firstly, to change the perception of pain in the brain and increase the threshold of pain in the spinal cord.[7]

Physicochemical properties, particularly lipid solubility and fraction un-ionized, dominate in determining distribution in the body and the rate of access to the biophase containing the drug receptors. Pharmacokinetic and pharmacodynamic properties of opioids of the fentanyl group, methadone, and morphine are characterized with respect to their features. Alfentanil and remifentanil have equilibration half-lives between plasma and effect site of about 1 minute. It is followed by fentanyl and sufentanil, with equilibration half-lives of almost 6 minutes. Methadone has a half-life of about 8 min.[9] However, morphine equilibrates with a half-life of 2 to 3 hours, and the slowest opioid with respect to plasma-effect site transfer is morphine-6-glucuronide (M6G), with an equilibration half-life of about 7 hours.[9]


Similar to opioids, endocannabinoids are also synthesized physiologically and released in the body by synapses to act on the cannabinoid receptors present on presynaptic endings to perform the following functions:[10][11]

  1. Decrease release of neurotransmitters
  2. Fire descending inhibitory pain pathways
  3. Decrease postsynaptic sensitivity and reduce neural inflammation

The pharmacokinetic properties of marijuana depend on its route of administration. Pulmonary inhalation of inhaled marijuana causes a maximum plasma concentration within minutes, and subsequently, psychiatric effects start within seconds to a few minutes, which reach a maximum after 15 and 30 minutes, and start tapering off within 2 to 3 hours. Following oral ingestion, psychiatric effects start with a delay of 30 to 90 minutes, reach their maximum after 2 to 3 hours, and last for about 4 to 12 hours.[12]

Issues of Concern


One of the main issues of concern regarding opioid use for pain treatment is the potential of drug abuse and addiction. This mainly occurs through damage in the glutaminergic and dopaminergic pathways in the brain.[13][14] The signs of Opioid addiction are compulsive drug-seeking behavior, taking drugs despite adverse social and physical effects, drug craving, and symptoms of withdrawal.[15][16] Importantly, opioid-use disorder is the leading cause of drug-related deaths in the United States of America (USA).[16] The treatment of opioid addiction is high resource intensive and prone to relapse.[13][17][18]

Furthermore, there are several other adverse effects of opioid use, including immunosuppression, obesity, respiratory depression, constipation, and miosis, to name a few.[7][19] Subsequently, patients develop tolerance to most side effects, except for miosis and constipation, which are problems the patient may have to live with or treat supportively while on opioids for pain management.[20] There are also some severe side effects, such as opioid-induced hyperalgesia and narcotic bowel syndrome.[21] Discontinuing opioids in a person dependent on them may lead to abstinence syndrome, a constellation of unpleasant symptoms, most common in the pediatric age group.[22] All of these are issues of concern regarding opioid use for pain management. 

There is a strong association between addiction and withdrawal, and subsequently, its consequent physical and psychological effects. In some cases, it can become difficult to identify actual chronic pain due to other causes and pain due to withdrawal in an addict. However, symptoms including yawning, sweating, lacrimation, and piloerection are strongly associated with drug withdrawal than with pain due to other conditions. Opioid withdrawal also causes an increase in baseline pain caused by other disorders. Withdrawal from short-acting opioids is mainly brief due to which physical symptoms reach their maximum intensity over a period of 36 to 72 hours and subsequently start reducing in intensity.[23]


Cannabis has been mostly restricted due to its psychotropic effect for pleasure-seeking and the stigma associated with it, thus causing it to be illegal in many countries along with its Schedule I status in the USA. Furthermore, the cultivation and production of cannabis have been banned for almost three-quarters of a century, thus impeding research and its use in medicine.[24] Cannabinoids have several short-term side effects, but tolerance to them develops eventually.[11][25] The long-term side effects of cannabis are harder to evaluate as they come primarily from recreational use.[11] Cannabis is better tolerated as compared to oral cannabinoids.[26] However, not much data is available for the efficacy of cannabinoids for treating pain and whether it is a safe substitute for opioids.[27] Additionally, if there is also an addiction potential associated with its use or not.

A psychoactive constituent of cannabis, 9-tetrahydrocannabinol or THC, is associated with cardiovascular disease, acute pancreatitis, cannabinoid hyperemesis syndrome, and when smoked, leads to lung disease.[28][29] It also leads to occupational injuries. Furthermore, its use during pregnancy has been associated with an increased risk of neonatal morbidity and death.[30] Its long-term use can lead to cognitive risks caused by the attenuation of gray matter in the brain.[31] Psychopathological effects of cannabis use have also been noted, including schizophrenia, acute psychosis, depression, bipolar disorder, and anxiety.[32] However, patients taking medical cannabis, most of them with chronic pain, have reported its health benefits, including improved sleep and pain management.[33]

Clinical Significance


The second and the third step of the World Health Organization's step ladder includes opioids for pain management.[34] They are used in gastrointestinal pathologies to alleviate pain, such as chronic pancreatitis and inflammatory bowel disease.[35] They are also used for pain associated with osteoarthritis, migraine, lower back, cancer, and post-operative pain. Their efficacy is proven through randomized clinical trials (RCT) for some of these conditions.[36][37][38] 


Cannabis is not approved by Food and Drug Administration (FDA) and is considered an illicit drug by the US drug enforcement agency (DEA). However, still, several US states permit its use in certain medical conditions.[39] Medical cannabis (MC) is used to treat migraines, chronic pain, back pain, arthritic pain, and pain associated with cancer and surgery.[39][40] Studies have shown that patients being treated for pain may successfully substitute cannabis for opioid medication; thus, this may positively curb the opioid epidemic.[41] Cannabinoids have also been shown to reduce neuropathic pain associated with different conditions and prevent diabetic neuropathic pain if given early in the disease course.[42][43][44] Cannabinoids also reduce inflammatory pain and thus can be used in conditions such as arthritis, sickle cell disease, cancer, and inflammatory bowel disease.[45][46][47][48]

Studies have shown that MC helps reduce the opioid dosage for patients being treated for non-cancer pain. It is also substituted in place of opioids to produce the therapeutic effect.[49][50][51] This opioid-sparing effect of cannabinoids is of great importance and warrants synergistic use of both rather than just one treatment modality for best results.

Other Issues

Marijuana, if used by an inexperienced user in large doses, can lead to symptoms including anxiety, paranoia, depersonalization, depressed mood, illusions, and hallucinations. Blood flow irregularities to the temporal lobe of the brain have also been observed in marijuana smokers.[52] There is also another concern related to the use of marijuana that its experience can lead to the use of other potentially more dangerous narcotic drugs.[52] 

Legal issues related to the use of cannabis have also led to the delay in research over its use, as only a few states allow it while others still have concerns over its use. 

Opioids use disorder has become an epidemic in the USA in recent years now. In addition, respiratory depression associated with opioid use has led to the loss of precious lives. Due to these reasons, efforts are being put into finding an ideal alternative to manage pain in patients with chronic and terminal diseases with the same and/or better efficacy, less potential for drug abuse and dependence, and a better benefit to risk ratio to opioids.

Enhancing Healthcare Team Outcomes

Chronic pain affects a person's lifestyle due to its somatic and psychological effects. Hence, a multidisciplinary team consisting of a pain medicine specialist, an internist, and a psychiatrist should manage these patients. The condition is best addressed with potent analgesics like opioids, and regular follow-ups for the side effects and changes in dosage as needed are required. Moreover, due to the fatal side effects of opioids, patients should be educated about the adverse signs and symptoms and the potential for drug abuse and dependence.

Article Details

Article Author

Noman Khalid

Article Editor:

Abhishek Singh


7/26/2022 12:21:18 AM



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