Opioids or Pain?

Medical advances keep us alive longer, but for some it is just living longer in pain. Opioids are the major drugs given to those with long-term chronic pain, but have limited usefulness because of tolerance and side-effects, and, of course, the underlying risks of addiction.

The risks of addiction with opioid treatments are real and a valid concern. For long-term use, the balance between potential addiction and relief from chronic pain determines the appropriateness of their use.

The choice to take opioids also depends on the type of pain experienced, and underlying causative disease, quality of life, and prognosis.

Opioids are powerful medications and significantly reduce pain – they decrease the perception of and reaction to pain, and increase tolerance to pain. However, they don’t work in everyone. Individual responses vary complicating their use, and the same dose can elicit variable levels of therapeutic effect in different individuals.

Dosing Opioids

Opioids exert their effects through receptors in the central and peripheral nervous system and in the GI tract. How an individual responds to a specific opioid therapy depends on the nature of the receptor it binds and affinity.

Long-term opioids reach a dose ceiling due to rapid onset of analgesic tolerance coupled with gradual tolerance to the side-effects of respiratory depression, nausea and decreased gastrointestinal motility.

Side-effects of Opioids

The patient who can tolerate the side-effects of an opioid drug gains more pain relief.

Opioids mediate variable unwanted central and peripheral side-effects – respiratory depression, nausea, sedation, euphoria/dysphoria, decreased gastrointestinal motility and itching.

Opioids can cause cough suppression, which can be both an indication for opioid administration or an unintended side effect.

How Tolerance Develops

Various factors influence a patient’s physiologic response to opioids, including the individual’s genetic makeup, concomitant medications, gut microflora, and how the individual opioid is metabolized.

Understanding tolerance mechanisms helps improve pain management and will help develop new drugs so opioids can be used more effectively.

Tolerance has two aspects: reduced efficacy of the drug at reducing pain and the patient’s ability to tolerate adverse effects. Both of these factors impact opiate-mediated pain relief.

If the patient on opioids becomes tolerant they no longer gain benefit in terms of pain relief as the drug has a reduced pharmacological effect with a higher dose needed for similar benefit

Conversely, tolerance can offer benefit as adverse effects decline with increased use.

The best opiate medicine provides sufficient pain relief and the patient can tolerate it in high doses.

If tolerance to the side-effects develops, treating pain is easier. If the rarer tolerance to pain relief occurs – failure to provide sufficient pain relief – this makes pain relief difficult.

Tolerance to pain relief occurs either because opioid receptors are reduced or act less effectively.

Opioids for Cancer Pain

Opioids are vital medicines for the palliative care of cancer patients. Cancer induced pain is separated into three types: acute, chronic and breakthrough pain. The mechanisms of cancer pain also influences the response to opioids – such as inflammatory pain, nociceptive pain, or neuropathic or mixed pain.

Even patients with similar types of cancer pain may require variable doses for pain control. Thus it is not just the pain itself, but other factors also influence the individual’s  response to opioids. These include the patient’s psychosocial status, concurrent medications they are taking, gender or genetic factors, and whether the patient is opioid naive or has previously been opioid tolerant.

Most cancer patients gain good relief from pain while on opioids. Tolerance to the analgesic effects of opioids does not develop as quickly as in those with other types of pain.

The reason to raise the dose of an opioid in a cancer patient is most likely to be due to the progression of disease generating further pain. Analgesic tolerance is rarely a limiting factor to the use of opioid

Breakthrough pain is managed using a  powerful fast-acting opioid such as intravenous morphine or transmucosyl fentanyl.

Patients with cancer pain may require higher doses of opioids to attain analgesia – tolerance develops – for a number of reasons: disease progression, metastasis, neuropathic pain or psychological factors such as anxiety.

Thin cancer patients respond worse to opioids than those with a normal body mass index.

Oxycodone is increasingly used in cancer pain because its main metabolic pathway is the inducible cyp3A4. Tolerance to oxycodone can develop with concomitant medications. Patients on stable doses of oxycodone with stable analgesia can suddenly develop increasing pain.

If the concomitant drug induces the cyp3a4 pathway, then it functions more efficiently and oxycodone is metabolised to moroxycodone, which is a less inactive metabolite. Then pain relief that the patient has will be less from the same drug.

Oxycodone is actively taken up into the brain so the brain concentration of oxycodone is a few times higher than in the plasma; the reverse is true for morphine. Because it is transported more efficiently analgesia is often better with oxycodone than morphine. So measuring plasma concentrations does not help determine efficacy.

Transporter systems regulate opioid transport across the blood brain barrier and dictate opioid efficacy and the development of tolerance. Genetic studies show a p-glycoprotein gene mutation causes a malfunction in the transporter and improves morphine analgesia.

Tolerance to Side-Effects

Choosing an appropriate opioid involves balancing how much pain relief the patient experiences and how they tolerate any side-effects related to the medication.

Boosting patient tolerance to unwanted side-effects improves their compliance as well as opiate efficacy. Lack of tolerance minimizes drug efficacy and impedes dose escalation.

Administering add-on treatments or choosing the most appropriate analgesic in a personalised medicine approach reduces the impact of unwanted side-effects of opioids.

Psychological Factors

Anxiety plays a role through the cholecystokinin receptor in all types of pain; it contributes more to pain intensity than depression. Administering repeated opioids induces tolerance as it chronically stimulating cholecystokinin receptors and induces tolerance. So cholecystokinin receptor antagonists may counteract this effect and improve opiate efficacy.

Increased tolerance is seen after adrenalectomy and hypophysectomy – it is reversed with ACTH – so some researchers suggest the HPA axis plays a role in opioid tolerance.

Chronic pain itself counteracts opioid tolerance and pain generates excitatory input that balances opioid effects.


Reducing Tolerance

Many different mechanisms influence tolerance. Some suggest candidate interventions for example if morphine binds the opioid receptor, then it does not enter the cell.

Chronic opioid exposure activates the glia and this is one mechanism that explains both hyperalgesia and tolerance. Glial inhibitors – minocycline, ibudiplast and pentoxifylline – can be used to limit tolerance, but don’t seem to prevent it.

Anti-opioid peptides counteract the opioid analgesic effects. Low doses of these opioid antagonists may reduce side-effects and tolerance to opioids.

Some studies indicate that opioid antagonists can reduce both opioid central effects – e.g. respiratory depression – and peripheral effects – constipation – depending on how they are administered. If naloxone is given with oxycodone then it blocks the opioid mu receptor in the gut, but when it gets to the liver it is metabolized. So there is no naloxone effect on naloxone on opioid effects on the brain and it does not inhibit the central effects of the opioid. But if  methylnaltrexone is given as well, the methyl group prevents the drug from getting into the brain, so the side-effects remain peripheral.

Naloxone prevents binding of the excitatory G-protein coupling to epinephrine and has non-opioid mediated effects.

NMDA receptor antagonists are the most promising drugs for fighting tolerance and some of them are already available.

Ketamine improves opioid analgesia for some patients when tolerance develops, but has very low bioavailability and a narrow therapeutic window.

The need for effective-long term analgesia remains. In order to develop new therapeutics and more novel strategies for use of current analgesics, the processes that mediate tolerance must be understood, including the potential pharmacokinetic (changes in metabolite production, metabolizing enzyme expression, and transporter function) and pharmacodynamic (receptor type, location and functionality; alterations in signaling pathways and cross-tolerance) aspects of opioid tolerance development.



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