Cannabis/Cannabinoids

Cannabis/Cannabinoids

PEP Topic 
Chronic Pain
Description 

Cannabinoids, compounds in the cannabis plant, bind to cannabinoid receptors and exert pharmacologic effects that stimulate appetite, exert antiemetic action, and have analgesic effects. Cannabinoids approved for use in the United States include dronabinol and nabilone. Cannabis compounds studied in regard to symptom management in patients with cancer have been in oral sprays, in forms for oral use, and in forms ingested through smoking. Note that not all cannabis formulations or methods of ingestion provide the same effects and results.

Likely to Be Effective

Research Evidence Summaries

Johnson, J.R., Burnell-Nugent, M., Lossignol, D., Ganae-Motan, E.D., Potts, R., & Fallon, M.T. (2010). Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. Journal of Pain and Symptom Management, 39(2), 167–179.

doi: 10.1016/j.jpainsymman.2009.06.008
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Study Purpose:

To compare the efficacy of a tetrahydrocannabinol:cannabidiol (THC:CBD) extract, a nonopioid analgesic endocannabinoid system modulator, and a THC extract to the efficacy of placebo in relieving the pain of patients with advanced cancer; to compare the safety and tolerability of the treatments with those of placebo

Intervention Characteristics/Basic Study Process:

Patients with cancer pain, who experienced inadequate analgesia despite chronic opioid dosing, were randomized to THC:CBD extract (n = 60 patients), THC extract (n = 58), or placebo (n = 59) for a two-week, multicenter randomized double-blind, placebo-controlled trial.

Sample Characteristics:

  • The sample was composed of 177 patients.
  • Mean patient age was 60.2 years.
  • Of all patients, 82 were female and 95 were male.
  • In the sample, the primary cancer sites were breast (29), prostate (24), and lung (20). In the sample, pain classifications included mixed pain (89), bone pain (65), neuropathic (39), visceral (37), and somatic/incident (18). Baseline morphine equivalents median was 120 mg.

Setting:

  • Multisite
  • Hospice, hospital, and university settings
  • The United Kingdom, Belgium, and Romania

 

Study Design:

Randomized, double-blind, placebo-controlled, parallel-group study

Measurement Instruments/Methods:

  • Numeric Rating Scale (NRS), 0–10
  • Brief Pain Inventory (Short Form) (BPI-SF)
  • European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-C30) Version 3.0
  • Patient-generated diary
  • Analysis of covariance (ANCOVA)

Results:

  • Compared to the placebo and THC groups, approximately twice as many patients in the THC:CBD group had an NRS reduction from baseline of at least 30% (THC:CBD = 23 patients [43%], THC = 12 patients [23%], placebo = 12 patients [21%]).
  • The THC groups showed a nonsignificant change, similar to the change in the placebo group.
  • In median dose of opioid background medication and in mean number of doses of breakthrough medication across treatment groups, authors observed no change from baseline.
  • Authors noted no significant group differences in sleep quality or nausea scores or in pain control assessment. However, the EORTC QLQ-C30 showed, compared to placebo, worsening of nausea and vomiting in the THC:CBD group. The EORTC QLQ-C30 showed no worsening of nausea and vomiting in the THC group.

Conclusions:

THC:CBD may be of benefit as an adjunct to opioid when pain is not fully controlled despite chronic opioid therapy. However, this conclusion warrants further investigation; the EORTC questionnaire showed a worsening of nausea and vomiting in the THC:CBD group, compared to the placebo group. In addition, patients in this study reported a consistent impairment of cognitive function. In addition, though authors reported at least a 30% reduction in NRS from baseline in the THC:CBD group, from baseline no change occurred, across treatment groups, in median dose of opioid background medication or mean number of doses of breakthrough medication.

Limitations:

  • Treatment models may have varied, country to country.
  • The study was very short, with a duration of only two weeks.

Nursing Implications:

THC:CBD extract—a nonopioid analgesic, endocannabinoid system modulator—may be a useful adjunct in managing the pain of patients who have inadequate analgesia from chronic opioids. However, one must consider the potential side effects (i.e. nausea, vomiting, impaired cognitive functions) that may occur as a result of adding this medication.

Johnson, J.R., Lossignol, D., Burnell-Nugent, M., & Fallon, M.T. (2013). An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. Journal of Pain and Symptom Management, 46, 207–218.

doi: 10.1016/j.jpainsymman.2012.07.014
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Study Purpose:

To investigate the long-term safety and tolerability of 9-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray and THC spray in relieving pain in patients with advanced cancer

Intervention Characteristics/Basic Study Process:

Patients who had previously participated in a two-week parent RCT to investigate the efficacy, safety, and tolerability of THC/CBD spray and THC spray in patients with cancer-related pain were invited to take part in the long-term, open-label, follow-up study. This study took place at 22 study sites in the United Kingdom and Belgium. Visits occurred at the conclusion of the RCT study or at extension study screening, 7–10 days later, then every four weeks, and at study completion or withdrawal. Adverse events, vital signs, blood sample analyses, changes in medication dosing and in current medical conditions were monitored at each visit. A pump action oromucosal spray was used to deliver the study medication. Each 100 uL actuation of THC/CBD spray delivered 2.7 mg of THC and 2.5 mg of CBD to the oral mucosa. Each actuation of THC delivered 2.7 mg of THC, and each actuation of placebo (in the parent RCT) delivered the excipients plus colorants.

Sample Characteristics:

N = 43  

MEAN AGE = 57.5 years for the THC/CBD group, 58.6 years for the THC group

MALES: THC/CBD: 59%, THC: 25%; FEMALES: THC/CBD: 41%, THC: 75%

KEY DISEASE CHARACTERISTICS: Breast (21%), prostate (16%), rectum (16%), lung (7%), and bone cancers (5%)

OTHER KEY SAMPLE CHARACTERISTICS: Those who had participated in the original RCT in Romania were not included in this study. The most commonly reported pain type was mixed pain, affecting more than half of all the patients, followed by neuropathic pain (37%) and bone pain (28%). Exclusion criteria included those with a history of severe cardiovascular, renal, hepatic, convulsive, or psychiatric disorder (other than depression associated with pain), patients currently taking levodopa, those pregnant or lactating or those not using adequate contraception, and those with oral cavity cancers or those whose previous treatments had included radiotherapy to the floor of the mouth.

Setting:

  • SITE: 22 study sites 
  • SETTING TYPE: Not stated   
  • LOCATION: United Kingdom and Belgium

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Palliative
  • APPLICATIONS: Elder care, palliative care

Study Design:

Patients self-titrated THC/CBD spray (n = 39) or THC spray (n = 4) to symptom relief or maximum dose and were assessed regularly for safety, tolerability, and evidence of clinical benefit.

Measurement Instruments/Methods:

  • Vital signs
  • Adverse events
  • Blood sample analyses
  • Pain assessment
  • Changes in medical condition
  • Current dose of study medication
  • European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)
  • Brief Pain Inventory-Short Form (BPI-SF)

Results:

The efficacy end point of change from baseline in mean BPI-SF scores for both “pain severity” and “worst pain” domains demonstrated an improvement at each visit in the THC/CBD spray patients. The EORTC QLQ-C30 scores demonstrated an improvement from baseline in the domains of insomnia, pain, and fatigue.

Conclusions:

Long-term use of the THC/CBD spray was generally well tolerated. No evidence was seen of a loss of effect for the relief of cancer-related pain with long-term use. Patients who continued the medication did not seek to increase their dose of THC/CBD or other pain medication over time, suggesting a useful benefit of cannabinoids in cancer-related pain.

Limitations:

Small sample (less than 100)

Findings not generalizable

No comparable information with the study group, making drawing conclusions from the results difficult

Discrepancy between patient continuation within the study and the level of satisfaction of clinicians with level of pain relief

Nursing Implications:

For patients with cancer-related pain, pain is a major issue. The adjuvant use of cannabinoids in patient with cancer-related pain could provide a great benefit. The proportion of patients reporting satisfactory analgesia was greater for the THC/CBD spray than placebo overall. The results of this study show that patients and investigators considered that maintenance or treatment with THC/CBD spray was justified by the clinical importance of pain management in patients with cancer-related pain.

Portenoy, R.K., Ganae-Motan, E.D., Allende, S., Yanagihara, R., Shaiova, L., Weinstein, S., . . . Fallon, M.T. (2012). Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: A randomized, placebo-controlled, graded-dose trial. The Journal of Pain: Official Journal of the American Pain Society, 13(5), 438–449.

doi: 10.1016/j.jpain.2012.01.003
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Study Purpose:

To obtain information about the dose response for analgesia and safety in a population with medical illness and pain that is inadequately controlled by an opioid

Intervention Characteristics/Basic Study Process:

Patients were randomly assigned to different-dose groupings of nabiximol or placebo delivered as an oral spray. Study design included a 5- to 14–day baseline period, five weeks of treatment titration, and a poststudy follow-up after two weeks. Patients received a daily call, from a voice recording system, that asked them to grade average pain. Patients continued the use of scheduled opioids and usual analgesics for the treatment of breakthrough pain. Patients who received at least one dose of the study drug were included in intent-to-treat analysis.

Sample Characteristics:

  • The sample was composed of 263 patients.
  • Mean patient age was 58 years. Age range was 20–93 years.
  • Of all patients, 51.7% were male and 48.3% were female.
  • Patients had active cancer and moderate to severe chronic pain despite opioid titration. Of all patients, 15% had breast cancer, 17.8% had gastrointestinal cancer, 17.8% had lung cancer, 12.2% had prostate cancer, 33.9% had some other cancer, and 3.3% had an unknown type of cancer.
  • Patients were excluded if they had a major psychiatric or cardiovascular disorder, epilepsy, or significant renal or hepatic impairment or if they were pregnant, lactating, or used inadequate contraception. Also excluded were those expecting to receive therapies that would change pain and patients who were currently using or had used marijuana, cannabinoid-based medications, or rimonabant within 30 days of study entry and were unwilling to abstain for the duration of the study.

Setting:

  • Multisite
  • Eighty-four study centers across North America, Europe, Latin America, and South Africa
     

Phase of Care and Clinical Applications:

  • Phases of care: multiple phases of care
  • Clinical applications: end-of-life care and palliative care
     

Study Design:

Randomized placebo-controlled, graded-dose trial

Measurement Instruments/Methods:

  • Data obtained in response to six daily questions delivered via interactive voice-recording system
  • Brief Pain Inventory (Short Form) (BPI-SF)
  • European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-C30) Version 3.0
  • Patient Assessment of Constipation Quality of Life (PAC-QOL)
  • Montgomery-Asberg Depression Rating Scale (MADRS)
     

Results:

  • Analysis of continuous responder rate favored the nabiximols groups (P = 0.035). However, this analysis was significant in the lower-dose groups only.
  • The adjusted mean change in pain score for the low-dose group favored nabiximols (P = 0.006).
  • Post hoc analysis that combed the low- and medium-dose groups showed a treatment difference in favor of nabiximols (P = 0.019). When weekly mean scores of average pain were compared across the groups, the low-dose group showed the greatest reduction, favoring nabiximols (P = 0.024).
  • Sleep disruption scores were comparable at baseline for all groups. When evaluated at the end of treatment, the significant treatment effect (P = 0.012) was attributed to the low-dose group (p = 0.003). 
  • The EORTC QLQ-C30 showed that nabiximols negatively affected cognitive functioning. In addition, compared to patients using placebo, patients using nabiximols experienced a significant amount of nausea and vomiting (P = 0.019). Authors noted that most nausea and vomiting occurred in the high-dose group (P = 0.0090).
  • Of nabiximol-treated patients, 29.5% experienced a serious adverse event. Of placebo-using patients, 24.2% experienced a serious adverse event.

Conclusions:

Nabiximols can be beneficial in the treatment of the refractory pain of patients with cancer. This study represents a start in regard to discovering the optimum dose effect and safety of nabiximols. In this study, low to medium doses were associated with the greatest effect.

Limitations:

  • The study lacked dose individualization; therefore, the study cannot provide the most accurate picture of analgesic efficacy or side effects.
  • The opioid-sparing effect could not be evaluated.
  • Investigators might have avoided adverse events by lowering the dose of opioid.
  • Reporting regarding sleep disruption could have been stronger if the study had used a validated tool.
  • Authors provided no analysis of differences regarding breakthrough pain or total opioid doses between groups.
  • According to the authors' power calculations, the study was underpowered and intention-to-treat analysis using last result forward could have had over- or underestimated effects.

Nursing Implications:

This study affects nursing by providing a potential treatment option for patients with opioid-refractory pain. Nurses should be able to recognize opioid-refractory patients. Nurses should be educated regarding this novel cannabinoid treatment, its administration, and its side effects. Nurses should be able to teach patients how to use nabiximols. 


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