Morphine: is it an ideal analgesic for cancer pain?

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Images copyright of Becci Jarvis

In order to answer the above question, we must first answer:

What constitutes an ideal analgesic?

An ideal analgesic should be capable of suppressing all types of pain first and foremost, but it should also affect other systems (e.g. the motor system) as little as possible, possess good bioavailability, and be easily metabolised as well as excreted, whilst exhibiting very little to no toxicity.

What is morphine?

Opioids have been used as remedies for the treatment of pain for thousands of years, some arguing their use as analgesics may have originated in Ancient Greece (the Greek word “opos” from which the word opium is derived, meaning juice, is thought to refer to the liquid that emanates from the unripe seed capsules of the poppy flower, Papaver somniferum, when it is scored), while others accredit the Sumerians, whom are believed to have grown poppy flowers and extracted opium from them towards the end of the 3 rd Millenium B.C (1,2,3) .Fast-forward to today, and opioids have become the most widely used analgesics, with morphine as the mainstay of all major severe pain treatment, including severe cancer pain and acute post-operative pain (4,5,6,7,8,9) .

Despite morphine’s widespread clinical use and well-established efficacy and safety in clinical practice, the use of morphine as an analgesic continues to spark debate on a number of issues, related to not only its method and timing of administration, but also to the addiction and tolerance it develops, as well as its undesired side effects (12,13,14,4) .

With today’s post I would like to delve in the topic and provide an overall view of an important issue clinicians and patients alike should consider:

Is morphine an ideal analgesic?

Victorian morphine shot

Victorian morphine shot

How is morphine’s way of action?

The majority of clinically-used opioids, such as morphine, act as full agonists on the Mu (μ) opioid receptor (MOR), a type of receptor of the superfamily called G-protein coupled receptor (GPCR).

Once the molecules of morphine are activating their receptors, these signal to downstream kinases (enzymes) such asphosphoinositide 3-kinase (PI3K), mediating a variety of physiological effects such as supraspinal analgesia, but also euphoria, sedation and respiratory depression amongst others (10,11) .

Pros and cons of morphine

Morphine is a very effective analgesic, providing pain relief that lasts on average 4 hours when administered intramuscularly, intravenously, or subcutaneously, and sometimes slightly longer when administered orally (up to 6 hours).

The most limiting factor in the use of morphine as an analgesic and greatest area of controversy, however, is the side-effects of morphine, associated with the differential anatomical distribution of the MOR, coupled with the activation of a wide variety of signalling pathways by morphine. Consequently, morphine is capable of inducing a myriad of side-effects (listed in Figure 1), most of them attributed to its peripheral action. (for a full insight on side effects and way of actions comparing opioids vs cannabinoids click here)

Moreover, administration and/or prescription of morphine can certainly lead to the development of dependence and tolerance, both clinically (e.g. in treatment following spinal cord injury) and recreationally, so that doses must be increases to reproduce the same analgesics effects overtime, which is however advice against due to a large array of withdrawal symptoms to deal with upon cessation.

Figure 1

Figure – Summary of organ system effects and side effects of morphine and surrogatesm, taken from Al-Hasani R & Bruchas MR, 2011

Figure – Summary of organ system effects and side effects of morphine and surrogatesm, taken from Al-Hasani R & Bruchas MR, 2011

Morphine for cancer patients

For patients suffering from cancer, where providing analgesic relief for the severe pains that are often associated with cancer (prevalence: 50-70 % in cancer patients undergoing active treatment) is prioritised over the side effects of analgesic drug treatment, morphine remains the gold-standard. (15,16)

This data should make us reflect upon the way Western medicine still look at cancer patients.

Fear and cancer industry have blinded us onto believing that is ok to deliberately bombard with toxic chemotherapeutics and radiations those whom already have a compromised system from the disease itself.

With the same logic, the clinic has little concerns in delivering a toxic and addictive drug like morphine to people whose bodies are fighting the damages of a cancer outgrowth.

By this I am not advocating against pain relief, especially at the final stages, but just prompt you to reconsider life with cancer; not only it is not necessarily leading to fatality, but is also a time during which patients have the rights to live a fulfilling life.

The high likelihood of cancer patients using this medication over an extended period of time makes medicating orally the preferred route, but this method of administration does not come without drawbacks. (16)

From a mere pharmacological view, the bioavailability of morphine via the oral route is poor (20-40 %), varying greatly between individuals. (17,18)

There are other issues regarding the use of morphine in the treatment of severe cancer pain, with respiratory depression associated with accumulation of morphine metabolite morphine-6-glucuronide (M6G) in cancer patients.

Thus, patients exhibiting renal dysfunction should be very aware of the risks associated with the use of this analgesic.

Sadly, little funding goes towards finding evidences from comparative trials of cannabis-based medication, which may possess advantages in terms of analgesic efficacy versus side effects, and, compared to morphine, might even provide a treatment to the spread of the cancer, inducing an overall relief for the patient.

However, it is known that Cannabis can be used also to lower the doses needed of morphine, which can be key both on side effects managements as well as lowering risks for tolerance.

Therefore at the present moment morphine remains as the first line therapy for the severe pain treatment in patients suffering from cancer. (16)

Many patients are now benefiting from cannabis analgesic and anti-prolific properties to manage their cancer, and they all claim this plant (vaporised, extracted in oils, infused, juiced or eaten raw),  has greatly improved their life, providing, along with the analgesic effect, a life devoid of side effects.

 

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References

1. Ballantyne JC & Mao J. Opioid analgesics therapy for chronic pain. The New England Journal of Medicine. 2003;349:1943-1953.

2. Fishman SM. Pain Question & Answer: Side Effects of opioid analgesics. The American Pain Foundation.

3. Brownstein MJ. A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci USA. 1993;90:5391-93.

4. Al-Hasani R & Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2011;115(6):1363-81.

5. World Health Organisation. Cancer pain relief. World Health Organisation.1986;Geneva.

6. Hanks G et al. Expert Working Group of the Research Network of the European Association for Palliative Care. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Canc. 2001;84(5):587-93.

7. Donnelly S et al. Morphine in cancer pain management: a practical guide. Support Care Cancer. 2002;10(1):13-35.

8. Allen P et al. Epidural morphine provides postoperative pain relief in peripheral vascular and orthopedic surgical patients: a dose-response study. Anesth Analg. 1986;65(2):165-70.

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10.Polakiewicz RD et al. mu-Opioid receptor activates signaling pathways implicated in cell survival and translational control. J Biol Chem 1998;273(36):23534-41.

11.Weihrauch D et al. Morphine enhances isoflurane-induced postconditioning against myocardial infarction: the role of phosphatidylinositol-3-kinase and opioid receptors in rabbits. Anesth Analg. 2005;101(4):942-9.

12.Zech D et al. Validation of World Health Organization guidelines for cancer pain relief: a 10-year prospective study. Pain. 1995;63(1):65-76.

13.Ventafridda V et al. A validation study of the WHO method for cancer pain relief. Cancer. 1987;59(4):850-6.

14.Portenoy, RK & Coyle, N. Controversies in the long-term management of analgesic therapy in patients with advanced cancer. Journal of Pain and Symptom Management. 1990;5:307-19.

15.Wiffen P & McQuay H. Oral morphine for cancer pain. Cochrane Database of Systematic Reviews. 2007(4).

16.Christo P & Mazloomdoost D. Cancer Pain and Analgesia. Ann NY Acad Sci 2008;1138:278-98.

17.Hoskin P, Hanks G, Aherne G, et al. The bioavailability and pharmacokinetics of morphine after intravenous, oral and buccal administration in healthy volunteers. Br J Clin Pharmacol. 1989;27(4):499-505.

18.Säwe J, Dahlström B, Paalzow L, et al. Morphine kinetics in cancer patients. Clin Pharmacol Ther. 1981;30(5):629-35.

Viola Brugnatelli

Viola Brugnatelli is a Neuroscientist specialised in Cannabinoid circuitry, GPCRs signalling, and neuropharmacology. Her academy and research training let her gain extensive experience on medical cannabis and phytoceuticals both from preclinical as well as clinical perspective. She works as a consultant and speaker at seminars, workshops & tutorials for MDs, Universities and individual patients. She has been raised by the concepts of equality, responsibility and love towards the environment, others and oneself. In her vision, collective human knowledge behold the power for overall improvement of life at all its forms, thus, it should be accessible and shareable. Viola is currently researching therapeutic potentials of terpenes at University College of Dublin, Ireland, and established since 2014 the Science Online Magazine Nature Going Smart.

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