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Objective 8: Understand how to assess patients with opioid resistant pain and what types of medication may be helpful to them.

What about patients whose pain does not seem to be relieved by opioid analgesics? Although the majority of patients with pain do get relief with appropriate use of opioids, some patients remain in pain. 

A careful analysis of the possible reasons for this lack of relief should be done.

1) First, has the patient had an adequate dose of an opioid? 

This simple question is too often neglected.

2)  Is the patient sedated by opioids but still in pain?

This is the clearest definition of opioid-resistant pain.

Titrate the opioid until either the pain is relieved or persistent sedation occurs without pain relief.

3) Was the patient's pain ever opioid responsive?

If so, assess the current administration of the medication. Has an unidentified problem developed?  For example, is oral absorption impaired by vomiting or are patches not adhering well? Is a caregiver withholding medication because of concerns that have not been adequately addressed?

4) Consider whether opioid tolerance has developed.

Remember, tolerance is defined as the need for a higher dose of a drug to produce the same effect. In a patient with stable pain, tolerance presents as decreasing duration and level of analgesic effect.

When tolerance is suspected in a patient whose pain previously responded to opioids, titrate the opioid to a higher dose. If this dose does not relieve the pain, consider changing to a different opioid (usually at one-half the equianalgesic dose) to see if a better analgesic effect can be obtained with reduced cross-tolerance.

Cochrane review: Opioid switching to improve pain relief and drug tolerability

5)  If you determine that the pain is indeed opioid-resistant, evaluate the cause of the pain.

Neuropathic pain (that is, pain caused by damage to nerves) is particularly likely to be opioid-resistant. Bone pain is the second most common cause of opioid-resistant pain. These, along with other types of chronic and acute pain, may require the use of adjuvant analgesics and other techniques to obtain relief. However, opioids are usually part of the "complete package" of pain relief for these patients.

Adjuvant analgesics are medications whose primary purpose is not analgesic but which have been found to have analgesic effects in selected situations.

There are three main categories of adjuvant analgesic medication:  antidepressants, anticonvulsants, and corticosteroids.

1. Antidepressants are useful in neuropathic pain as well as many cases of chronic pain whatever the etiology.  The analgesic effect of antidepressants may occur at lower doses and more quickly than the antidepressant effects.  Relief obtained from antidepressants does NOT indicate that the pain was caused by depression or that the patient was even depressed.  The mechanism of action is independent.

  • Tricyclic antidepressants were the first type to be shown to be effective as adjuvant analgesics. Amitriptyline (Elavil) is the most extensively studied, but also has the highest anticholinergic and sedating side effects. Desipramine is a useful alternative. These are usually started at quite low doses (5-10 mg and titrated clinically.
  • Dual action antidepressants [venlafaxine (Effexor) and duloxetine (Cymbalta)] have also shown benefit. These are dosed and titrated in the same way as for depression.
  • SSRIs have not consistently been found to be useful.

Cochrane Review: Antidepressants for neuropathic pain

2. Anticonvulsants are especially effective for neuropathic pain. They are thought to work through their membrane-stabilizing effect. 

The agents most commonly used are gabapentin (Neurontin) and pregabalin (Lyrica).  Valproic acid has also shown efficacy.  Carbamazepine (Tegretol) and oxycarbamazepine (Trileptol) are particularly used for lancinating pain, such as trigeminal neuralgia. 

Fast Facts: Gabapentin for Neuropathic Pain

3. Corticosteroids, especially in high doses, are useful in cases of tumor infiltration into nerve or bone, as well as other refractory pain syndromes.  Long-term adverse effects may occur, so duration and dose are kept to a minimum. However, these effects are less of a concern in terminally ill patients.

4. Other alternatives for refractory cases include antiarrthymics, alpha-2 agonists, and NMDA receptor antagonists.

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