Notes and research for Marijuana and Cancer Pain Talk.

I spoke at the Alfond Cancer Center at 6 pm on Tuesday, October 25, 2016 on pain and marijuana use. These are my extended notes including studies I cited.
Casket joke: What would you want them to say? Doctor, Teacher, realist.
Discussing Pain
 Who I am.

1. Naturopathic Doctor
2. Colon Cancer Survivor? (I prefer the term “careful person”)

• Researcher Does marijuana help with cancer pain?

1. No. -side note on politics and medicine.
2. Maybe. -nausea research.

• What is pain?

1. A definition of pain. Unpleasant sensation. “physical suffering or discomfort caused by illness or injury”
2. a) Dental work b) broken arm c) vagovasal response to needles d) “gas pains” post-surgery.

• Tolerance is based on predictability, expectation, and duration.

1. Uncontrolled, random, unending pain
2. Torture is “the action or practice of inflicting severe pain on someone as a punishment or to force them to do or say something” it’s horrible but at least you know when and why.

• What causes the pain in cancer?

1. The mass vs. the mind.

“ In the subgroup of 22 patients who underwent the full cycle of 4 treatments, the mean VAS anxiety score decreased from 6.77 to 2.28 (P <.000001) and the mean VAS pain score from 4.4 to 2.32 (P = .091). Overall, the sessions were felt helpful in improving well-being, relaxation, pain relief, sleep quality and reducing anxiety.”

2. Not limited to cancer. Knee surgery outcomes depend on a) expection b) anxiety, c) depression, d) the skill of the surgeon.
3. Not a learned behavior. Touch and sugar on neonatals.

• Standard treatments for cancer

1. How well studied are the opiods?
2. How well done is end of life care?
3. Prior to hospice, are we taking care of patients?

• Tracking, meeting and treating pain

Other natural Treatments for Cancer Pain:
A. Ice Locally Proximally
B. Heat Locally Full body Distant
C. Capsaicin Local depletion of substance P. Along entire nerve root
D. Massage

1. Proximal to the area (upstream and down)
2. On the opposite side
3. On the spinal column
4. On the feet
5. On the ear

E. Prayer/Reiki

1. Any area
2. Hands on/Hands off
3. Distant, specifically (give time and frequency)

• Cortisone shots

1. Proximal
2. Into nerve roots
3. Much simpler that nerve cutting
4. Saline injections may be as effective (nerve pressure)

• TENS units

1. Muscle fatigue and natural opiod release
2. At nerve root to fatigue nerve pathway

• Anti-anxiety medication

1. Anticipatory pain relief
2. Many natural options: valerian, hops,passion flower, etc.

• Muscle relaxants

1. Muscle clenching due to pain builds lactic acid=more pain
2. Natural option Kava releases muscles and lowers anxiety

• Meditation

1. Jon Kabat Zinn
2. Women (colon and gynecologic cancers) experienced significant improvements in mood
3. Meditation outperforms groups.
4. Ipads during chemo for meditation-average distress dropped 46% (p < 0.0001).
5. Telomere length is maintained.

• Where does marijuana fit in?

1. Do you mind the side effects?
2. Do you want the side effects?
3. Are you cachexic?
4. Are you nauseous?
5. Have you experienced relief before?

Pain
How much is objective?
Patients experiencing high levels of pain before surgery should be informed of the chances of improvement by having a TKA (total knee arthroplasty). A validated psychological screening tool that separates depression and anxiety is recommended as part of the pre-operative assessment stage. Patients presenting with symptoms of depression and anxiety should be identified and consulted before a TKA.
How much is subjective?
Based on cut-off scores for the Neonatal Infant Pain Scale, infants receiving skin-to-skin contact during IM injection were more likely to display low pain after injection; and during recovery
Sucrose is effective for reducing procedural pain from single events such as heel lance, venipuncture and intramuscular injection in both preterm and term infants.
How well have we studied the opiods?
Data gathered in this review showed that hydromorphone had a similar effect on participant-reported pain intensity as reported for oxycodone and morphine. Participants generally achieved no worse than mild pain after taking hydromorphone, which is comparable with the other drugs. It produced a consistent analgesic effect through the night and could be considered for use in people with cancer pain experiencing sleep disturbance. However, the overall quality of evidence was very low mainly due to risk of bias, imprecision of effect estimates and publication bias.
How well have we studied end of life care?
often was not implemented properly, and had instead become a barrier to good care; it made over 40 recommendations, including education and training, research and development, access to specialist palliative care services, and the need to ensure care and compassion for all dying patients. In July 2013, the Department of Health released a statement that stated the use of the LCP should be "phased out over the next 6-12 months and replaced with an individual approach to end of life care for each patient".The impact of opioids was a particular concern because of their potential influence on consciousness, appetite and thirst in people near the end of life. There was concern that impaired patient consciousness may lead to an earlier death, and that effects of opioids on appetite and thirst may result in unnecessary suffering
Meditation

1. Jon Kabat Zinn http://umassmed.edu/cfm/stress-reduction/mbsr-8-week-online-live/
2. “Women (colon and gynecologic cancers) experienced significant improvements in sex-related distress (p < .001), sexual function (p < .001 and p < .01), and mood (p < .001)”
3. “ women in MBCR reported greater reduction in mood disturbance (primarily fatigue, anxiety and confusion) and stress symptoms including tension, sympathetic arousal and cognitive symptoms than those in SET. They also reported increased emotional and functional quality of life, emotional, affective and positive social support, spirituality (feelings of peace and meaning in life) and post-traumatic growth (appreciation for life and ability to see new possibilities) relative to those in SET,
4. meditation iPads during the chemotherapy session. Among those who accepted the iPads, average distress dropped 46% by the end of the session (p < 0.0001).
5. TL in the intervention group was maintained whereas it was found to decrease for control participants. There were no associations noted between changes in TL and changes in mood or stress scores over time.
6. For those already trained in the practice of meditation, a retreat appears to provide additional benefits to cellular health beyond the vacation effect.

Marijuana cancer 752
+cochrane 7
THC cancer 565

• Cochrane 5

Marijuana cancer pain 150
Cannabinoids bind not only to classical receptors (CB1 and CB2) but also to certain orphan receptors (GPR55 and GPR119), ion channels (transient receptor potential vanilloid), and peroxisome proliferator-activated receptors. Cannabinoids are known to modulate a multitude of monoamine receptors. Structurally, there are 3 groups of cannabinoids. Multiple studies, most of which are of moderate to low quality, demonstrate that tetrahydrocannabinol (THC) and oromucosal cannabinoid combinations of THC and cannabidiol (CBD) modestly reduce cancerpain. Dronabinol and nabilone are better antiemetics for chemotherapy-induced nausea and vomiting (CINV) than certain neuroleptics, but are not better than serotonin receptor antagonists in reducing delayed emesis, and cannabinoids have largely been superseded by neurokinin-1 receptor antagonists and olanzapine; both cannabinoids have been recommended for breakthrough nausea and vomiting among other antiemetics. Dronabinol is ineffective in ameliorating cancer anorexia but does improve associated cancer-related dysgeusia. Multiple cancers express cannabinoid receptors directly related to the degree of anaplasia and grade of tumor. Preclinical in vitro and in vivo studies suggest that cannabinoids may have anticancer activity. Paradoxically, cannabinoid receptor antagonists also have antitumor activity. There are few randomized smoked or vaporized cannabis trials in cancer on which to judge the benefits of these forms of cannabinoids on symptoms and the clinical course of cancer. Smoked cannabis has been found to contain Aspergillosis. Immunosuppressed patients should be advised of the risks of using "medical marijuana" in this regard.
Schmerz, Cochrane Review, this year:
Out of initially 108 studies 9, with a total of 1561 participants suffering from advanced or end stage diseases, were included...The outcome results for cannabis/cannabinoids vs. placebo in patients with cancer were not significant for the 30 % decrease in pain (RD: 0.07; 95 % confidence interval (CI): - 0.01 to 0.16; p = 0.07), caloric intake (SMD: 0.2; 95 % CI: - 0.66 to 1.06; p = 0.65) or sleep problems (SMD: - 0.09; 95 % CI: - 0.62 to 0.43; p = 0.72).Change in appetite was significant for the treatment of HIV (SMD: 0.57; 95 % CI: 0.11-1.03; p = 0.02), but not for treatment of cancer (SMD: 0.81; 95 % CI: - 1.14 to 2.75; p = 0.42). Nausea/vomiting (SMD: 0.20; 95 % CI: - 0.03 to 0.44; p = 0.09) and health-related quality of life (HRQoL; SMD: 0.00; 95 % CI: - 0.19 to 0.18; p = 0.98) did not show significant differences in the therapy of the two diseases. For the outcomes of tolerability the results were not significant for occurrence of dizziness (RD: 0.03; 95 % CI: - 0.02 to 0.08; p = 0.23) or psychiatric diseases, such as hallucinations or psychosis (RD: - 0.01; 95 % CI: - 0.04 to 0.03; p = 0.69) in the therapy of cancer.  Dronabinol vs. megestrol acetate showed a superiority of megestrol in the therapy of cancer-associated anorexia for the endpoints change of appetite (49 vs. 75 %; p = 0.0001), weight gain (3 vs. 11 %; p = 0.02), HRQoL (p = 0.003) and tolerability (p = 0.03). There was no difference in the safety of the therapies (p = 0.12). In the treatment of HIV-associated wasting syndrome megestrol acetate was better than dronabinol for the endpoint of weight gain (p = 0.0001), whereas tolerability and safety did not differ. In the therapy of Alzheimer's dronabinol was better than placebo in the endpoint of weight gain according to one study (n = 15). A difference between herbal cannabis and synthetic cannabinoids, analysed by one study (n = 62) could not be found.
Also Schmerz, this year:
cannabinoids were superior to placebo in the reduction of mean pain intensity with SMD - 0.10 (95 % CI - 0.20- - 0.00, p = 0.05, 13 studies with 1565 participants), in the frequency of at least a 30 % reduction in pain with an RD of 0.10 [95 % CI 0.03-0.16, p = 0.004, 9 studies with 1346 participants, number needed to treat for additional benefit (NNTB) 14, 95 % CI 8-45] and in the frequency of a large or very large global improvement with an RD of 0.09 (95 % CI 0.01-0.17, p = 0.009, 7 studies with 1092 participants). There were no statistically significant differences between cannabinoids and placebo in the frequency of at least a 50 % reduction in pain, in improvement of health-related quality of life and in the frequency of serious adverse events. Patients treated with cannabinoids dropped out more frequently due to adverse events with an RD of 0.04 [95 % CI 0.01-0.07, p = 0.009, 11 studies with 1572 participants, number needed to treat for additional harm (NNTH) 19, 95 % CI 13-37], reported central nervous system side effects more frequently with an RD of 0.38 (95 % CI 0.18-0.58, p = 0.0003, 9 studies with 1304 participants, NNTH 3, 95 % CI 2-4) and psychiatric side effects with an RD of 0.11 (95 % CI 0.06-0.16, p < 0.0001, 9 studies with 1304 participants, NNTH 8, 95 % CI 7-12).
CONCLUSION:
Cannabinoids were marginally superior to placebo in terms of efficacy and inferior in terms of tolerability.
Another Cochrane Review, this year, Nausea and vomiting only:
We included 23 RCTs. Most were of cross-over design, on adults undergoing a variety of chemotherapeutic regimens ranging from moderate to high emetic potential for a variety of cancers. The majority of the studies were at risk of bias due to either lack of allocation concealment or attrition. Trials were conducted between 1975 and 1991. No trials involved comparison with newer anti-emetic drugs such as ondansetron. Comparison with placebo People had more chance of reporting complete absence of vomiting (3 trials; 168 participants; RR 5.7; 95% CI 2.6 to 12.6; low quality evidence) and complete absence of nausea and vomiting (3 trials; 288 participants; RR 2.9; 95% CI 1.8 to 4.7; moderate quality evidence)
People reported a preference for cannabinoids rather than prochlorperazine (7 trials; 695 participants; RR 3.3; 95% CI 2.2 to 4.8; I(2) = 51%; low quality evidence)
Nurses Cochrane Review:Cannabinoids are effective in controlling CINV, and oral THC and smoked marijuana have similar efficacy. However, smoked marijuana may not be accessible or safe for all patients with cancer. Also, these drugs have a unique side-effect profile that may include alterations in motor control, dizziness, dysphoria, and decreased concentration.Conclusions: This synthesis shows that cannabinoids are more effective than placebo and comparable to antiemetics such as prochlorperazine and ondansetron for CINV
European Review from 2008:
From 12 749 initially identified papers, 30 fulfilled the inclusion criteria for this review, with demonstration of superiority of the anti-emetic efficacy of cannabinoids compared with conventional drugs and placebo. The adverse effects were more intense and occurred more often among patients who used cannabinoids. Five meta-analyses were carried out: (1) dronabinol versus placebo [n=185; relative risk (RR)=0.47; confidence interval (CI)=0.19-1.16]; (2) Dronabinol versus neuroleptics [n=325; RR=0.67; CI=0.47-0.96; number needed to treat (NNT)=3.4]; (3) nabilone versus neuroleptics (n=277; RR=0.88; CI=0.72-1.08); (4) levonantradol versus neuroleptics (n=194; RR=0.94; CI=0.75-1.18); and (5) patients' preference for cannabis or other drugs (n=1138; RR=0.33; CI=0.24-0.44; NNT=1.8). The superiority of the anti-emetic efficacy of cannabinoids was demonstrated through meta-analysis.
Here’s the Problem:
Based on available evidence, we could find that psychoeducational interventions, music interventions, acupuncture plus drug therapy, Chinese herbal medicine plus cancer therapy, compound kushen injection, reflexology, lycopene, TENS, qigong, cupping, cannabis, Reiki, homeopathy (Traumeel), and creative arts therapies might have beneficial effects on adult cancer pain. No benefits were found for acupuncture (versus drug therapy or shame acupuncture), and the results were inconsistent for massage therapy, transcutaneous electric nerve stimulation (TENS), and Viscum album L plus cancer treatment. However, the evidence levels for these interventions were low or moderate due to high risk of bias and/or small sample size of primary studies. Conclusion. CAM may be beneficial for alleviating cancer pain, but the evidence levels were found to be low or moderate. Future large and rigor randomized controlled studies are needed to confirm the benefits of CAM on adult cancer pain.
Cancer Pain, from 2001:
20 randomised controlled trials were identified, 11 of which were excluded. Of the 9 included trials (222 patients), 5 trials related to cancer pain, 2 to chronic non-malignant pain, and 2 to acute postoperative pain. No randomised controlled trials evaluated cannabis; all tested active substances were cannabinoids. Oral delta-9-tetrahydrocannabinol (THC) 5-20 mg, an oral synthetic nitrogen analogue of THC 1 mg, and intramuscular levonantradol 1.5-3 mg were about as effective as codeine 50-120 mg, and oral benzopyranoperidine 2-4 mg was less effective than codeine 60-120 mg and no better than placebo. Adverse effects, most often psychotropic, were common.

CONCLUSION:

Cannabinoids are no more effective than codeine in controlling pain and have depressant effects on the central nervous system that limit their use. Their widespread introduction into clinical practice for pain management is therefore undesirable.
Free article:
No large trials examined cannabinoids in cancer pain and chronic non-malignant pain

What is already known on this topic

Three quarters of British doctors surveyed in 1994 wanted cannabis available on prescription
Humans have cannabinoid receptors in the central and peripheral nervous system
In animal testing cannabinoids are analgesic and reduce signs of neuropathic pain
Some evidence exists that cannabinoids may be analgesic in humans

What this study adds

No studies have been conducted on smoked cannabis
Cannabinoids give about the same level of pain relief as codeine in acute postoperative pain
They depress the central nervous system
The effect of marijuana and placebo on pain tolerance was compared in cannabis-experienced and naive subjects. A statistically significant increase in tolerance was observed after smoking marijuana. Although there was no statistically significant interaction between the drug effect and having had previous cannabis experience, there was a definite trend towards a greater increase for the experienced (16%) compared to the naive group(8%).

Pain detection thresholds were altered unpredictably with high THC doses, but analgesia as indicated by pain tolerance was less than that after diazepam and placebo. In three subjects low-dose THC (0.022 mg/kg) was a better analgesic than placebo but not diazepam. Six subjects preferred placebo to low-dose THC as an analgesic; this group experienced increases in subjective surgical pain and were submissive, rigid, and less introspective with high State Anxiety