Sorry to be a pain, but…

Written by Graham Lappin  |  Visiting Professor of Pharmacology, University of Lincoln, Lincoln, UK  |  [email protected]

There is, we are told, an opioid addiction crisis. The problem is most acute in the USA,¹ and it also seems to be increasing here in the UK.² Many commentators attribute the cause to aggressive marketing and overprescribing by health professionals, but I would like to look at this from a different direction.

I will preface the paragraphs that follow by stating that I have just self-medicated on 30 mg of codeine, with 1 g of paracetamol or acetaminophen, depending upon where in the world you live. On some days I take higher doses, and I have done for many years. The reason for my medication stems from chronic pain caused by tissue and bone damage following a serious motorcycle accident. As I have got older, osteoarthritis has exacerbated the condition. I have a simple, but stark, choice: endure what it feels like to have ice-water injected into my veins and broken glass into my ankle joints, or the drowsiness of high doses of codeine. It is the codeine that invariably wins.

I have tried other drugs, but a combination of codeine and paracetamol or ibuprofen works best for me. However, the painful truth is that the choice is only a choice in regard to which opioid-based drugs I take, as there is no other realistic alternative. From oxycodone, to tramadol, to morphine, to fentanyl, they all target opioid receptors and they all have their own range of unpleasant side effects. Opioids in the form of plant extracts have been used as analgesics for around 3,000 years.  As a former drug developer this is remarkable, not because of some romantic notion of ‘ancient wisdom’ but because over all that time no realistic alternatives have appeared, in what other therapeutic area is this the case? Imagine, for example, if we did not have beta and calcium channel blockers and still relied solely on digoxin.³

The causes of chronic pain are wide and varied, as reflected in the broadness of its two subcategories: nociceptive pain, associated with tissue damage in all its diverse forms; and neuropathic pain, associated with damage to the somatosensory nervous system itself. The problem with opioid-type drugs is that they do not discriminate the root cause of pain, but rather treat the symptoms by targeting the presynaptic mu, delta, or kappa opioid receptors, located primarily in the brain and spinal cord. Sometimes anti-inflammatories are used to treat the root cause of pain, but this is a discussion for a different time. Unlike many other therapeutic areas, available pain therapeutics have not been designed with root-cause specific drug targets in mind. The only recent nonopioid targeted analgesics are cone snail peptide derivatives, such as ziconotide (N-type calcium channel antagonist) and Xen2174 (noradrenaline transporter antagonist), which is currently in clinical development.⁴ Administration of these drugs occurs via the intrathecal route, so their use is restricted to specific clinical needs. The current analgesic landscape, however, may be changing with the emergence of monoclonal antibody (mAB) technology.

A major advantage of mAB is that because of their high specificity, interaction is likely to be exclusive to the drug target, thus reducing the effects of off-target toxicity. A consequence of mAB high specificity means it is necessary to identify unique drug targets and understand their pharmacology. An example of such a mAB is erenumab, a migraine treatment, engineered to bind to calcitonin gene-related peptide, and other therapeutic mAB aimed at pain are in the pipeline.⁵ One of the most promising therapeutic options, and of personal interest, is tanezumab aimed as a treatment for osteoarthritis. The drug target is nerve growth factor, a key mediator in peripheral pain.

As with any therapeutic intervention, nothing is perfect. The gastrointestinal tract is impermeable to mAb. As a result, administration is typically intravenous or subcutaneous, which is more invasive than an oral formulation, but personally, the discomfort of an injection pales into insignificance compared to that of chronic pain. They are also relatively expensive, although costs may decrease as they become more commonplace. Development of tanezumab has not been without its problems, and it was on clinical hold for a short time. It is now back in development and cautious optimism seems warranted.

I recognise that aggressive marketing by the pharmaceutical industry and perhaps some laissez-faire doctors may be a contributing factor to the rise in opioid addiction, but I feel the bigger crime is a chronic lack of investment in therapeutic pain research (pun intended). I hope that the scene is changing and that it does not take another 3,000 years for those changes to occur.

REFERENCES

1. Van Zee A. The promotion and marketing of oxyContin: Commercial triumph, public health tragedy. Am J Public Health. 2009;99(2):221-7.
2. Matthews-King A; The Independent. Health department launches ‘landmark review’ of prescription drug addiction in UK. 2018. Available at: https://www.independent.co.uk/news/health/prescription-drug-addiction-uk-review-health-department-jeremy-hunt-care-a8174706.html. Last accessed: 1 May 2018.
3. Withering W. An Account of the Foxglove and Some of Its Medical Uses. 1785. Available at: http://library.umac.mo/ebooks/b2834599x.pdf. Last accessed: 1 May 2018.
4. Grant B; The Scientist. Novel Analgesics at a Snail’s Pace. 2018. Available at: https://www.the-scientist.com/?articles.view/articleNo/51206/title/Novel-Analgesics-at-a-Snail-s-Pace/. Last accessed: 1 May 2018.
5. Yeh JF et al. Monoclonal antibodies for chronic pain: A practical review of mechanisms and clinical applications. Mol Pain. 2017;13:1-14.

Further Reading

Lappin, G. Dr Graham Lappin’s Science Blog. Available at: https://glappin59.wixsite.com/blog.