A hypothesis
Evaluation of the hypothesis





Opiates are among the most powerful analgesic agents. The prescribing of buprenorphine, codeine, morphine, fentanyl, and in particular of tramadol, has increased exponentially since the mid 1990’s.1,2 The growth of the use of tramadol has been particularly remarkable since its introduction in 1994, perhaps also because of its lower propensity to cause unpleasant side effects such as nausea and vomiting.

It has long been known that opiates are potentially addictive thereby limiting their medical use, making them susceptible to abuse and adding to the global drug problem. Nevertheless, their use has been extended to the management of chronic pain. Unsurprisingly, this has been paralleled by a growth of opioid-related morbidity and mortality that has most recently raised international attention.3

Most research has been focused on opiate addiction. This is believed to be linked to positive memories associated with the pleasurable effects of opiates and negative memories associated with dysphoria during opiate withdrawal, leading to the compulsive opiate-seeking behaviour characterising addiction.

A large amount of data has been gathered in respect to neuroadaptations. This is the process whereby the body compensates for the presence of a chemical in the body so that it can continue to function normally.

Since the discovery of synaptic plasticity—the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity—strong overlaps between neural and cellular substrates of learning and addiction have been recognised.4

The current notion of addiction supports the idea that aberrant forms of drug-induced synaptic plasticity and learning in the brain drive addictive behaviours.5

Glutamate is the major excitatory neurotransmitter in the brain and it plays an integral role in opiate addiction. This relates, in part, to the fact that addiction is a disorder of learning and memory and glutamate is required for most types of memory formation. As opiate addiction develops, the addict becomes conditioned to engage in addictive behaviours, and these behaviours can be triggered by opiate-associated cues during abstinence, resulting in relapse. Some medications for opiate addiction exert their therapeutic effects at glutamate receptors, especially the NMDA receptor.6

Not all patients prescribed opiates become addicted. A bigger issue can be that the drugs can cause further symptom pain. This can be seen in some patients to whom opiates were initially prescribed for a problem that is not rapidly selflimiting such as mechanical backache.

One study in male rats highlighted that prolonged pain is an unrealised and clinically concerning consequence of the abundant use of opioids in chronic pain. It found that a short course of morphine starting 10 days after injury doubled the duration of chronic constriction injury months after morphine ceased. Initiation and maintenance of this multi-month prolongation of neuropathic pain was mediated by morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1β (IL-1β), stressing the critical importance of microglia.7

Patients’ functional impairment appears to remain both significant and long-standing leading to further opiates prescribing often combined with other medications such as amitriptyline, gabapentin and pregabalin.


A hypothesis

One hypothesis is that exogenous opiates induce over-expression of the opiate receptors, a group of inhibitory G protein-coupled receptors with opioids as ligands. In parallel, the physiological endogenous production of the opioids—dynorphins, enkephalins, endorphins, endomorphins and nociceptin—is suppressed.

The two mechanisms will cause pain to become more significant when the concentration of the exogenous opiates drop. Then an inability to adapt to the nociceptive signal leads to a prolongation of pain. Therefore, this hypothesis is that the initiation of opiates to treat conditions that are likely to be not rapidly self-limiting may expose the patient to increased risk of chronic pain deeply affecting patients’ quality of life as well as increasing the risk of addiction.


Evaluation of the hypothesis

The process of adaptation to painful or intense stimulations is most evident in our daily lives. An intense light may be disturbing and even painful if we are coming from a dark room, yet we get used to it promptly. If we wear sun glasses, once we remove them the unpleasant sensation will recur.

An intense smell of ammonia may be painful. We can stop this by pinching our nose, but as soon as we re-open the nasal cavities the pain will relapse. If we don’t try avoiding the pungent smell, this will slowly but surely fall in the background. The same principle applies to noise and thermic stimulations. It is unlikely that this interference in the adaptation process is inconsequential. The consequences may be far greater if we are unable to correct the problem, or the problems, to which we are supposed to adapt.

Painful stimuli are helpful and provide the central nervous system with crucial information about a possible danger. The response to which may, for instance, be a change in posture, retracting one arm, so as to limit the body damage.

In such a key and primitive defence mechanism, an effective communication between neurons is paramount. Blinding the nociceptive signal with an exogenous opiate is likely to cause a response that aims to re-establish a communication between the neurons involved. In view of the plasticity of the CNS, a learning process is also likely to take place and leave a long-lasting memory.



The immediate consequence of this hypothesis is that the physician should do the utmost to avoid the use of opiates to treat conditions that are likely to be chronic, without a well-defined culprit, and without prior exploration with the patient of the potential implications. The use of opiates may lead to hyperalgesia which is a state of nociceptive sensitisation caused by exposure to opioids as well as opioid-prolonged neuropathic pain, several other side effects and complications such as addiction.

This may leave clinicians with a dilemma about how best to deal with chronic pain and when to suggest use of other types of analgesia. Especially as the use of pregabalin and gabapentinoid in chronic pain has been recently questioned both in terms of safe prescribing and effectiveness.3,8,9

Yet, clinicians should where possible avoid the development of chronic pain, promptly identifying the cause of the pain and promote healing.

Healing of lesions, such as surgical and traumatic lesions, mainly involves the clotting process, inflammation, cell proliferation and tissue remodelling. Healing time depends on the extent of the damage and its localisation, such as the depth of the wound.

Firstly, we should make maximum effort to identify medical conditions that can slow the healing process. Delayed healing may be due to the failure of one or several steps in the healing process, caused by metabolic, cardiovascular, infectious, immunological or drug-related disorders.

Secondly, we must review drugs that may antagonise the healing process. The principal drugs that can slow wound healing are cytotoxic antineoplastic and immunosuppressive agents, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and anticoagulants. In practice, when wound healing is delayed, it is best to keep in mind that a drug may be the cause, and to consider withdrawing any drug or drugs known to have this effect, in order to allow the wounds to heal.

Particular attention should be paid to the commonly prescribed NSAIDs. For instance, it has been demonstrated that when NSAIDs are used to reduce the associated inflammation, swelling and pain that peak one to two days post-injury in acute muscle injuries, early administration of NSAIDs has been shown to delay muscle regeneration and contribute to loss of muscle strength after healing.

Furthermore, NSAID administration inhibits several important muscle regeneration processes and downregulated multiple cytoprotective proteins known to inhibit the intrinsic pathway of programmed cell death.10



When faced with the challenges of subacute pain, or acute pain less likely to resolve promptly, GPs should make maximum effort to identify medical conditions that can slow the healing process. They also must review drugs that may antagonise the healing process such as cytotoxic antineoplastic and immunosuppressive agents, corticosteroids, NSAIDs and anticoagulants.

They also must be mindful that opiates may cause chronic pain and addiction and that the benefits of pregabalin and gabapentinoids in nonneuropathic pain are limited, if of any relevance, and probably overwhelmed by the potential downsides.

Prompt physiotherapy advice may be also beneficial. At all times, patients should be kept informed about pros and cons of the suggested management strategies.

Edoardo Cervoni, GP, Central Park Surgery, Balfour Street, Leyland, Lancashire

Conflict of interest: none declared.



1. Qureshi ZP, Haider MR, Rodriguez-Monguio R, et al. Opioid Prescription Drug Use and Expenditures in US Outpatient Physician Offices: Evidence from Two Nationally Representative Surveys. Cancer Ther Oncol Int J 2017; 3(3)

2. Ruscitto A, Smith BH, GuthrieB. Changes in opioid and other analgesic use 1995–2010: Repeated cross-sectional analysis of dispensed prescribing for a large geographical population in Scotland. European Journal of Pain 19: 59–66

3. Gomes T, Juurlink DN, Antoniou T, et al. Gabapentin, opioids, and the risk of opioid-related death: A populationbased nested case-control study. PLoS Med 2017; 14(10).

4. Ting-A-Kee R, Van der Kooy D. The neurobiology of opiate motivation. Cold Spring Harb Perspect Med 2012; 2(10)

5. Dacher M, Nugent FS. Opiates and plasticity. Neuropharmacology 2011; 61(7)

6. Peters J, De Vries TJ. Glutamate mechanisms underlying opiate memories. Cold Spring Harb Perspect Med 2012; 2(9)

7. Grace PM, Strand KA, Galer EL, et al. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci U S A 2016; 113(24): E3441–50

8. Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. Drugs 2017; 77: 403–26

9. Mathieson S, Chiro M, Maher CG, et al. Trial of Pregabalin for Acute and Chronic Sciatiatica. Engl J Med 2017; 376: 1111–20

10. Bryant AE, Aldape MJ, Bayer CR, et al. Effects of delayed NSAID administration after experimental eccentric contraction injury - A cellular and proteomics study. PLoS One 2017; 12(2)