Chronic Non-Cancer Pain

Seriousness of medical condition(s)

The Pain Australia website reports that 3.24 million Australians were living with chronic pain in 2018. 53.8% are women (1.74 million) and 46.2% are men (1.50 million). For the majority (56%) of Australians living with chronic pain, their pain restricts what activities they can undertake and substantially reduces their quality of life). It was shown that long term pain was the reason for 40% of visits in a primary care setting (Mantyselka et al., 2001). Chronic pain can be a serious and complex disabling condition for many patients with various chronic conditions (e.g. neurological and musculoskeletal disorders and cancer (local or metastatic)

Who could benefit from this treatment?

Intended for patients with treatment-resistant chronic pain when other treatment and management strategies have not completely resolved symptoms, failed, are contraindicated or caused side effects.

Clinical justification for using Medicinal Cannabis

  1. The medicinal cannabis’s suitability for the intended indication and
  2. the medicinal cannabis’s efficacy and expected benefits

 

Relief from chronic pain is by far the most common condition cited by patients presenting to medical doctors (GPs and Specialists) for the medical use of cannabis. Ilgen et al. (2013) reported that 87% of participants in their study were seeking medicinal cannabis for pain relief. Light et al. (2014) reported that 94% of Colorado medical marijuana ID cardholders indicated “severe pain” as a medical condition. In addition, there is evidence that some patients are replacing the use of conventional pain medications (e.g. opioids) with cannabis. For example, one recent study reported survey data from a Michigan medical marijuana dispensary showing that medicinal cannabis use in patients with chronic pain was associated with a 64% reduction in opioid use (Boehnke et al., 2016). Similarly, recent analyses of prescription data from Medicare part D enrolees in states with access to medicinal cannabis suggest a significant reduction in the prescription of conventional pain medications (Bradford and Bradford, 2016).

 

Patients indicate that they have been substituting all or some of their prescribed opiate-based medications with cannabis. Bruce et al. (2017) conducted semi-structured interviews and identified three main patterns of MC use: alternative, complimentary, or as a tapering-off mechanism to prescribed medications. Specific reasons to use MC as alternative to opioids included acting more quickly, reducing potential harm, better management of symptoms, and fewer side effects. Corroon et al. (2017) utilized an online questionnaire to survey 1248 cannabis users. About half of them (46%) reported using cannabis as a substitute for prescription drugs; the most frequent substitution was narcotics/opioids (35.8%). Reiman et al. (2017) examined the use of cannabis as a substitute for opioid-based medication in an online survey of 2897 cannabis patients. Thirty percent of the sample (n=841) reported using an opioid-based pain medication currently or in the past 6 months; of these, 61% were also using cannabis. The vast majority of these patients (97%) reported using less opioids when using cannabis and experienced more tolerable side effects with cannabis than with opioid medications alone (92%). They also reported preferring cannabis to opioids for the treatment of their condition and would consider choosing only cannabis if it was more readily available (93%).

 

Goggin et al. has shown that for each of the opioids investigated (codeine, morphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl and buprenorphine), cannabis use was associated with statistically significant lower urinary opiate levels than in samples without indicators of marijuana use (Goggin et al., 2019). Combined with the survey data showing that pain is one of the primary reasons for use of medicinal cannabis, the most recent report suggests that a number of patients are replacing the use of opioids with cannabis

 

Systemic Reviews:

Five good-to-fair quality systematic reviews were performed to date. Of these, Whiting et al. (2015) was the most comprehensive, both in terms of the target medical conditions and in terms of the cannabinoids tested. Whiting et al. included studies that compared cannabinoids to usual care, placebo or no treatment conditions. Where RCTs were unavailable for a condition or outcome, nonrandomized studies including uncontrolled studies were considered. The rigorous screening approach used by Whiting et al. (2015) led to the identification of 28 randomized trials in patients with chronic pain (2,454 participants). Twenty-two of these trials evaluated plant-derived cannabinoids (nabiximols, 13 trials; plant flower that was smoked or vaporized, 5 trials; THC oromucosal spray, 3 trials; and oral THC, 1 trial), while 5 trials evaluated synthetic THC (i.e. Nabilone). All but one of the selected primary trials used a placebo control, while the remaining trial used an active comparator (Amitriptyline). The medical condition underlying chronic pain was most often related to a neuropathy (17 trials); other conditions included cancer pain, multiple sclerosis, rheumatoid arthritis, musculoskeletal issues, and chemotherapy-induced pain. Analyses across 7 trials that evaluated Nabiximols and one that evaluated the effects of inhaled cannabis suggested that plant-derived cannabinoids increase the odds for improvement of pain by approximately 40% vs the control (odds ratio [OR] 1.41; 95% confidence interval [CI] 0.99-2.00; 8 trials). The effects did not differ significantly across pain conditions, although it was not clear if there was adequate statistical power to test for such differences. Only one trial (n of participants =50) that examined inhaled cannabis was included in the effect size estimates (Whiting et al., 2015). This study (Abrams et al., 2007) also indicated that cannabis reduced pain vs a placebo (OR 3.43; 95%CI 1.03-11.48). It is worth noting that the effect size for inhaled cannabis is consistent with a separate recent review of 5 trials of the effect of inhaled cannabis on neuropathic pain (Andreae et al., 2015).

 

The National Academy of Sciences, Engineering, and Medicine’s 2017 publication, The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research provided a significant contribution by synthesizing the existing evidence base for the therapeutic use of cannabinoids. In this book, a conclusion on the therapeutic effects of Cannabis and Cannabinoids states that:

 

There is conclusive or substantial evidence that cannabis or cannabinoids are effective:

  • For the treatment of chronic pain in adults (cannabis)
  • As antiemetics in the treatment of chemotherapy-induced nausea and vomiting (oral cannabinoids)
  • For improving patient-reported multiple sclerosis spasticity symptoms (oral cannabinoids)

 

There is moderate evidence that cannabis or cannabinoids are effective for:

  • Improving short-term sleep outcomes in individuals with sleep disturbance associated with obstructive sleep apnoea syndrome, fibromyalgia, chronic pain, and multiple sclerosis

 

Guidelines for treatment of chronic non-cancer pain:

The TGA’s Guidance for the use of medicinal cannabis in the treatment of chronic non-cancer pain in Australia states that “overall, we can be moderately confident that CNCP patients receiving medicinal cannabis are more likely to achieve 30% and 50% reductions in pain and to report a reduction in pain ratings than patients given a placebo”. However, due to heterogeneity of clinical trials used in meta-analyses, varying definitions of CNCP, small sample sizes, variability in cannabis products, doses, methods of administration the overall benefit is hard to determine. Refer to the TGA Guidelines for further information about the treatment of chronic non-cancer pain.

 

The Canadian Pain Society recommends using cannabinoids as third-line analgesic agents in the treatment of neuropathic pain (Moulin et al. 2014). As per the European Pain Federation position paper, cannabis-based medicines (CBM) can be considered as third-line therapy for chronic neuropathic pain. CBM should be regarded as an individual therapeutic trial, when established treatments have failed, for all other chronic pain conditions (cancer, non-neuropathic noncancer pain) (Hauser et al., 2018).  Also, cannabinoids are recommended by the European Federation of Neurological Societies as second or third-line agents for refractory cases of central neuropathic pain in multiple sclerosis (Attal et al, 2010).

 

The 1:20 THC: CBD formulation offers a gentle starting dose for cannabis-naïve patients and elderly patients making it a feasible option.

  1. any unknown or expected adverse effects, risks and safety issues & d. related toxicology:

A systematic review by Whiting et al. (2015) stated in their conclusions that “Cannabinoids were associated with an increased risk of short-term adverse effects”.

According to the Guidance for the Use of Medicinal Cannabis in Australia: Overview, Therapeutics Good Administration (2017):

Cannabis is not appropriate for patients who:

  • Are under the age of 25 (with the exception of intractable epilepsy or severe pain syndrome)
  • Have a personal history or strong family history of psychosis
  • Have a current or past cannabis use disorder, or active substance use disorder
  • Have unstable respiratory or cardiovascular disease (including angina, peripheral vascular disease, cerebrovascular disease, arrhythmias)
  • Are pregnant, planning to become pregnant, or breastfeeding

 

Cannabis should be authorized with caution in patients who:

  • Smoke tobacco
  • Have risk factors for cardiovascular disease
  • Are heavy users of alcohol
  • Are taking sedating medications or any other medication metabolized by the CYP450 pathway
  • At risk or have liver disease

 

Drug Interactions – CYP P450 Enzyme System

THC and CBD are metabolized by Cytochrome P450 enzyme system, including CYP1A2, CYP2C9, CYP2D6, CYP2C19 and CYP3A4. Based on in vitro and animal studies with cannabis, there is a potential for interactions with the medications metabolized by the P450 enzymes (2C9, 2C19, 3A4). It’s notable, however, that the inhibitory effects in vitro and in animal models were only seen at exposures significantly higher than the maximum observed in clinical trials. For instance, in clinical trials were Sativex® has been taken concomitantly with other drugs metabolized by the Cytochrome P450 enzyme system, no clinically apparent drug-drug interactions have been seen in these trials at clinical doses. In an in vitro study with 1:1% (v/v) THC botanical drug substance (BDS) and CBD BDS, no relevant induction of the Cytochrome P450 enzymes was seen for human CYP1A2, CYP2C9, CYP2C19 and CYP3A4 in human hepatocytes at doses of up to 1µM (314ng/mL) (Stout and Cimino, 2014).

 

Potential drug interactions

Increasing THC concentration:

Examples of inhibitors:

– Antidepressants (e.g. Fluoxetine, Fluvoxamine)

– Proton Pump Inhibitors (e.g. Omeprazole)

– Cimetidine

– Macrolides (Clarithromycin, Erythromycin)

– Antimycotics (e.g. Itraconazole, Fluconazole, Ketoconazole, Miconazole)

– Calcium Antagonists (e.g. Diltiazem, Verapamil)

– HIV protease inhibitors (e.g. Ritonavir)

– Amiodarone

– Isoniazid

– Grapefruit juice

 

Increasing CBD concentration:

– Metabolized by CYP 2C19 and CYP 3A4

– Bioavailability could be increased by many of the same substances as for THC

 

Decreasing THC and CBD concentration:

  • CYP 2C9 and 3A4 Inducers accelerate THC and CBD metabolism
  • Examples of inducers:

– Rifampicin

– Primidone

– Carbamazepine

– Phenobarbital

– Phenytoin

– Rifabutin

– Saint John’s Wort

 

Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen in the study by Gaston et al (2017) on interactions between cannabidiol (Epidiolex®) and commonly used antiepileptic drugs. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with supraphysiological doses of CBD (e.g. 1000mg/kg).

 

  • Caution with blood thinners like Warfarin, Heparin, Clopidogrel (Plavix)
  • Additionally, pharmacodynamic interactions should be expected between cannabis and drugs with sympathomimetic activity (tachycardia, hypertension), central nervous system depressants (drowsiness, ataxia), and drugs with anticholinergic effects (tachycardia, drowsiness).

 

Many of these drug interactions can be mitigated in complex patients with polypharmacy by slowly titrating cannabis.

Approved treatments for this medical condition

Chronic pain management requires a holistic multi-modal approach that incorporates lifestyle changes and behaviour modification. This management is well documented in the Therapeutic guidelines – Attachment 6, Chronic Pain Syndrome Medication_ Antidepressants, Other, Anticonvulsants, Analgesics, Nonsteroidal Anti-inflammatory Drugs. See also attachment “Principles of prescribing for persistent non-cancer pain”, Milton L Cohen, 2013.

There are a number of analgesic medications currently available over the counter and by prescription that include:

  • Analgesics/Opioids: Paracetamol, Codeine, Oxycodone, Fentanyl, Morphine, Buprenorphine and Pethidine
  • Non-steroidal anti-inflammatory drugs: Ibuprofen, Naproxen sodium, Diclofenac, Indomethacin, and Ketoprofen
  • Anticonvulsants: Gabapentin and Pregabalin

Why is medicinal cannabis appropriate for use?

Opioids:

Many meta-analyses have found little evidence that this class of drugs is effective for the treatment of chronic pain (https://www.nps.org.au/professionals/chronic-pain). Certainly, there are individual patients who experience significant relief of their pain and improvements in function with opioid therapy. But there are many more patients who are not helped or are harmed by opioids.

There is a substantial body of evidence which demonstrates that whilst opioids are fundamental drugs in the treatment of pain, paradoxically they increase sensitivity to pain as a consequence of chronic use (Lee at al., 2011; Doverty et al., 2001 a&b). Opioid-induce hyperalgesia is now widely recognized (Yi & Pryzbylkowski 2015). Ironically, the traditional mode of treating pain is unwittingly making matters worse for these patients. Furthermore, opioids are a leading cause of dependency, addiction, morbidity (sedation, increased falls, etc.), mortality (deaths from accidental or non-accidental overdose, trauma with falls such as head injuries) and hospitalization in Australia.

It is well recognized that there are issues with opioid overuse (https://www.racgp.org.au/afp/2016/december/prescription-drug-abuse-a-timely-update/). Recently, this has been discussed in Therapeutic Goods Administration (TGA) consultation paper: Prescription S8 opioid use and misuse in Australia – options for a regulatory response.

There is evidence, albeit not consolidated, suggesting that medicinal cannabis may be “opioid sparing” (Goggin et al., 2019). More research is warranted to assess this opioid-sparing effect, which if proven, will be a welcoming way to help patients withdraw from opioids in future.

 

NSAIDs:

It is well known that patients with chronic pain do not always respond to standard NSAIDS analgesics. Moreover, gastrointestinal side effects such as indigestion, stomach upset (including nausea or feeling sick) or stomach pain are commonly caused by NSAIDs. Chronic use of NSAIDs can also cause ulcers and bleeding in the stomach and other parts of the gastrointestinal tract (gut).

 

Gabapentinoids:

In the search for alternatives to opioids, clinicians may have lowered their thresholds for prescribing gabapentinoids for patients with various types of acute, sub-acute and chronic non-cancer pain (Goodman and Brett, 2017). For some of these patients’ non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated, and for others paracetamol or NSAIDS do not offer adequate relief or are considered ‘not strong enough’. There is, however, little evidence of gabapentinoids relieving pain that has no neuropathic component (Shanthanna et al., 2017, Moore et al., 2009). Evidence shows that gabapentinoids provide some relief of neuropathic pain for some patients (NNT = 7.7 for pregabalin and 6.3 for gabapentin) (Finnerup et al., 2015) however, use of these medicines for chronic non-neuropathic pain conditions such as low back pain is not supported by evidence (Shanthanna et al., 2017, Moore et al., 2009, Goodman and Brett, 2017). Compounding this is evidence that some prescribed gabapentinoids are being misused, and recent evidence shows that Gabapentinoid misuse has become a globally recognised problem (Evoy et al., 2017). Analysis of the European Medicines Agency EudraVigilance database shows that gabapentinoid misuse events were rising over the period from 2006-15 (Chiappini and Schiffano 2016). Increases in pregabalin misuse have been seen in Germany (Gahr et al., 2013) and Sweden (Schwan et al., 2010) and in Kentucky, recreational gabapentin use increased 2950% between 2008 and 2015 (Smith et al., 2015). Australian data on gabapentinoid misuse remain sparse, but available sources suggest the problem is growing. In Victoria, overdose deaths where pregabalin was a factor have increased since 2012. Data from the Victorian Coroner’s Court Overdose Deaths Register showed that there were no deaths involving pregabalin in 2009–12, however in 2013 there were 17 deaths involving pregabalin, with another 26 deaths recorded in 2014, and 31 deaths recorded in 2015 (Dwyer J., 2016). Suicidal ideation, as well as mood disturbance and depression, are also known adverse events associated with pregabalin (Arana et al. 2010, Hall et al., 2015) and resulted in a safety warning by the US Food and Drug Administration (FDA) in 2008 (Katz R., 2008). Supratherapeutic doses may produce sedation, dissociation, relaxation, contentment, numbness, uninhibited behaviour, or audio and visual hallucinations (Schjerning et al., 2016, Evoy et al., 2017). Abrupt discontinuation of gabapentinoids has been shown to produce withdrawal symptoms (such as insomnia, headache, nausea, anxiety, hyperhidrosis (excessive sweating) and diarrhoea, indicative of physical dependence (Evoy et al., 2017). One study noted withdrawal symptoms in about one-third of pregabalin abuse cases (Gahr et al., 2013). Administering benzodiazepines during withdrawal does not seem to relieve symptoms.

 

Studies specifically assessing patients with opioid use disorder demonstrated 15%–22% misused gabapentin, while problem use of pregabalin varied widely, from 3%–64% (Evoy et al., 2017). This is particularly concerning, as concomitant use of gabapentin with opioids has been associated with a substantial increase in the risk of opioid-related death, probably because of additive respiratory depression (Gomes et al., 2017).

 

The World Health Organization is currently reviewing the need for international control of pregabalin due to its potential for dependence, abuse and harm to health (https://www.who.int/medicines/access/controlled-substances/ecdd_39_meeting/en/)

References