A Painful Paradox

A Painful Paradox

Research discovers what we always knew – opiate users DO feel pain and regular opiate use may even lead to an increased sensitivity to pain. Researcher, Dr. Tim Mitchell from the National Addiction Centre, lays bare the research anyone who works with opiate users should know about – pain and pain relief for opiate users.

For thousands of years, opium and its derivatives have been used for their powerful pain-killing effects. But now scientists believe that repetitive opioid use may actually lead to an increased sensitivity to pain. This paradoxical difference – between the short and long-term effects of opioids – could have importance consequences for anyone who uses opioids regularly.

In order to understand how people respond to pain, researchers need a way of inducing pain in experiments that carries no serious threat of damage to the volunteer. A popular method for doing this is the cold pressor test, in which people are asked submerge their forearm in a bucket of icy cold water (~1°C) and keep it there for as long as possible. The amount of time a person can withstand the cold water is used as a measure of pain tolerance.

When researchers at the University of Adelaide in Australia used the cold pressor test to explore how opioids affect pain tolerance, the results were astonishing. In one study, they compared pain tolerance in a group of people maintained on methadone with a group of drug-free control subjects. You might expect that the methadone group – with an average daily dose (62 mg) sufficient to kill an opioid-naïve person – would have been able to tolerate pain better than the control group. The opposite pattern was found. The control group lasted an average of about 1 minute in the cold water; the methadone group averaged less than 20 seconds.

Other studies have shown that a reduced tolerance to pain applies not only to people on methadone, but also to people receiving other opioids such as morphine and buprenorphine (Subutex). There are also indications that heightened pain sensitivity can persist even when a person stops using opioids. But do opioids actually cause an increased sensitivity to pain? Or are people with a greater sensitivity to pain just more likely to use opioids in the first place?

To establish whether opioids actually cause an increase in pain sensitivity, scientists would need to make a group of people become dependent on opioids and look at whether pain tolerance changes as a consequence. Since studies of this kind would be considered unethical in humans, they have instead been conducted in animals. The results clearly show that opioids do cause an increased sensitivity to pain. Rats exposed to successive morphine injections show a gradually lowering of pain tolerance; rats exposed to injections of saline show no change.

If opioids can cause an increased sensitivity to pain, then what are the implications for regular opioid users? One issue of particular concern is what happens when people who use opioids – especially those maintained on methadone or other substitute opioids – require opioids for the treatment of pain. The danger is that such people may receive inadequate pain relief if standard protocols for treating pain are applied.

To explore this possibility, the University of Adelaide researchers used the cold pressor test to look at how much pain relief people on methadone get when they are given intravenous morphine. Whereas morphine was found to drastically increase pain tolerance in drug-free control subjects, it had minimal effect in methadone users – even at morphine dose levels well in excess of those normally given post-operatively.
These findings suggests that, in addition to being abnormally sensitive to pain in the first place, opioid users are likely to receive very little pain relief from standard doses of morphine.

To make matters worse, some clinicians may be reluctant to prescribe adequate opioid doses to people who use opioids. Reasons for such reluctance could include fears of side effects (e.g., respiratory depression, overdose), a belief that methadone and other maintenance medications may contribute to pain relief, or uncertainty about patient motivations (e.g., drug-seeking). Patients may be reluctant to disclose a history of opioid use for fear that this may impact on how they are treated. For these reasons, the management of pain in people who use opioids is complicated.

Beyond the challenges of pain management, having an abnormal sensitivity to pain may have wider implications for opioid users’ well-being. Pain is not merely a physiological process – it’s an unpleasant subjective experience that can have a powerful negative effect on mood. A persistent sensitivity to pain could be associated with negative mood states (e.g., dysphoria). If so, it’s possible to imagine a cycle whereby heroin use leads to greater pain sensitivity and more negative mood states, which in turn lead to further compensatory heroin use, and so on. In several experiments where people have taken opioids repeatedly over many days, a gradual shift towards dysphoria has been observed. However, the psychological consequences of an abnormal sensitivity to pain remain unclear, and more research is needed.

Leaving aside such speculation, it is clear that the way we understand opioid tolerance may need to be revised in light of these findings. Tolerance is often thought of as a single process, whereby a drug’s potency declines with repeated use; in other words, a process of desensitisation. But now it appears there may be a second process at work – at least in the case of how opioids affect our ability to perceived pain – involving a gradual increase in sensitivity to pain; a process of sensitization. This would help to explain why opioid users are not only less responsive to the pain killing effects of morphine than opioid-naïve individuals, but also more sensitive to pain to begin with.

In recent years, significant progress has been made in trying to understand the changes that cause opioid dependence at a cellular level – including those that give rise to changes in pain sensitivity. The hope is that such understanding may help to develop more effective pharmacological interventions for both the treatment of pain and opioid dependence.

One strategy already being investigated involves co-administering opioids with a class of drugs known as NMDA antagonists. These drugs block activity at the NMDA receptor, which is involved in the development of opioid tolerance. Studies in animals suggest that NMDA antagonists can help to prevent the development of opioid tolerance and associated increases in pain sensitivity. But does this also work in humans?

In the United States, a combination drug product called Morphidex® – a 1:1 mixture of morphine and the NMDA antagonist dextromethorphan intended for use as an analgesic – has been put into development by US drug company Endo Pharmaceuticals. To date, results from clinical trials of this drug have been mixed. Despite early findings that people on Morphidex® for pain may require lower doses than people getting morphine alone, a more recent and definitive study found no such advantage.
One priority is to develop better treatment strategies for the management of pain in opioid users.
Realising that standard morphine dosing protocols are unlikely to be effective for such people, the University of Adelaide research group are now investigating where other opioids such as remifentanil provide better pain relief. Beyond seeking improvements in how drugs are used clinically for pain relief, another priority is to achieve greater awareness of how opioids may alter pain sensitivity – amongst both opioid users and the medical community. In these endeavors, it is crucial that the voices and experiences of opioid users are heard – especially those who have ever sought treatment for pain. With such cooperation it can be hoped that a solution to this painful paradox – short term gain, long term pain – may be uncovered.

BP says: Hospitals could follow other countries lead (France) and have guidelines created around how to administer pain relief to those who are dependant on opiates. Perhaps it is something Drug User Groups can tackle – discussing these issues on a regional level with local Primary Care Trusts, to united pushing for National guidelines. Go get ‘em!