In 1986, the World Health Organization (WHO) disseminated an algorithm for the use of analgesic medications in cancer patients with pain.[1,2] This simple pharmacologic tailoring approach could be used by physicians in both developed and developing countries (Figure 1). When used appropriately, this three-step analgesic ladder has been effective in approximately 70% to 90% of patients.[3-7]
Unfortunately, these guidelines, while adhering to the KISS principle (keep it short and simple), did not provide guidelines for the appropriate use of adjuvant medications such as tricyclic antidepressants, anticonvulsants, steroids, membrane stabilizing agents, etc., and did not specify the optimal management of the patients who do not respond. Additionally, many patients throughout the world do not, in fact, benefit from this approach because opioid medications are unavailable to them, or because barriers to the successful implementation of the WHO ladder exist.
These barriers include actual and perceived governmental regulations on opioid prescribing practices, deficits in the knowledge of health care providers, caregivers, and pharmacists on how and when to use opioid agents, religious beliefs, the fear that opioids are harmful to patients and may hasten their demise, and the pervasive misunderstanding that the use of opioids inevitably leads to tolerance and addiction. The problem is probably greater than previously perceived; it has recently been estimated that only 50% of patients actually benefit from the WHO ladder because of the barriers described previously.[9-12]
Physicians should, above all, do no harm and learn to use the least invasive and least costly therapies. We should do what works for our patients. For cancer patients, single therapies like the analgesic ladder approach should be optimally administered whenever pain is reported. When the WHO fails, alternative therapies should be available.
Untreated cancer pain remains an enormous and truly unfortunate problem. It has been estimated that more than 70% of all patients dying from cancer experience pain in the end stage of their disease. In 1995, in the United States, approximately 547,000 patients died from their cancer. If the 70% estimate is correct, 382,000 of these patients suffered from intractable pain. Furthermore, if the survey data showing a less than 50% response rate to the WHO guidelines is correct, then approximately 190,000 patients experiencing severe pain from their disease would have had their pain well controlled if their caregivers used the simple guidelines of the analgesic ladder of the WHO. It also means that more than 190,000 patients did not.
If the WHO guidelines for the treatment of cancer pain were the only option, a very significant proportion of cancer patients in the United States would die suffering from intractable pain. Clearly, there is a place for other therapies. Recognizing the failure of the WHO guidelines to effectively treat all patients with cancer pain, many physicians have incorporated a fourth rung to the WHO ladder for patients who fail systemic opioid tailoring (Figure 2).
After the failure of opioid tailoring, it is imperative that physicians do not abandon their patients, either by walking away or by resorting to terminal sedation. Treating physicians must choose therapies that work and abandon those therapies that dont work, and not the patients.
Therapies not included in the WHO guidelines include psychological and complementary approaches such as relaxation, massage, distraction, meditation, prayer, etc., and more invasive analgesic approaches such as temporary nerve blocks; spinal infusions of opioids, local anesthetics and/or alpha-2 agonists; neuromodulatory techniques; and various somatic and sympathetic chemical, surgical, and thermal neurodestructive procedures. Table 1 lists possible interventions that can be used in appropriately indicated patients.
Many of the techniques with which pain specialists treat pain in noncancer patients today we learned from our experience with treating the pain of cancer patients. We have learned to use the least invasive and less costly therapies before resorting to more invasive and more costly therapies. We have learned that very few patients become addicted to opioids. We have learned to do what works and abandon what does not work.
These lessons are the foundation for treatment strategies now used for the noncancer pain patients. Indeed, a pain treatment continuum, though recommended for noncancer patients, also might be used for those patients who are suffering from cancer pain (Figure 3).
Spinally Administered Opioids for Cancer Pain
When the systemic delivery of opioids is not working because of dose-limiting side effects or because pain appears to be poorly responsive to opioids, a trial of intraspinal opioids, alone or in combination with nonopioids such as local anesthetics or clonidine(Drug information on clonidine) (Duraclon), may be indicated. Before a trial of intraspinal opioids, patients should undergo a trial of sequential oral or transdermally administered opioids (Table 2). Because most cancer pain syndromes cause constant pain in patients, it is recommended that long-acting opioids be prescribed on a timed, around-the-clock basis, and not on an as-needed basis.
There should be medication allowance for pain that breaks-through the baseline level of the long-acting medication. Rescue medication for breakthrough pain should be a short-acting opioid. If pain is uncontrolled, the dose of the long-acting opioid is adjusted upwards.
Physicians treating cancer patients with pain should be educated about the principles of opioid therapy, including the role of the oral route, equianalgesic doses, methods of dose titration, and side-effect management. Administration of opioids via the intravenous or subcutaneous route can be more costly than intraspinal delivery of opioids and should not be automatically recommended as an alternative to intraspinal opioid delivery.
Not all pain is the same and certainly not all pain syndromes react to opioids in the same way. Pain syndromes are usually categorized as nociceptive (either visceral or somatic), neuropathic, or a combination of both (so-called mixed pain). Nociceptive pain is believed to be sustained by activation of primary afferent nociceptors. It appears to be usually responsive to opioid therapy.
Neuropathic pain, on the other hand, is not mediated by nociceptors and may be responsive to opioids at doses equivalent to those for nociceptive pain syndromes, or at higher doses, or it may not respond to opioids at all.[16-18]
Neuropathic pain syndromes in cancer patients that may not respond to usual doses of opioids or may not respond at all include neural involvement by tumors; radiation fibrosis of the head and neck, the brachial plexus, intercostal nerves, the lumbar or lumbosacral plexus, the superior hypogastric plexus, or the celiac plexus; neurologic sequelae of chemotherapeutic agents; the peripheral neuropathies; and damage to neural structures by surgical interventions.
Once it has been established that a cancer patient does not respond adequately to systemically administered opioids, the patient may be a candidate for a trial of intraspinal analgesia. The term intraspinal analgesia is preferred over intraspinal opioid in this context because nonopioid agents are now available for intraspinal use.
These nonopioid agents include the local anesthetics and the alpha-2 agonist, clonidine. Other agents that might be used, but are considered experimental, include somatostatin(Drug information on somatostatin) (Zecmil) or the somatostatin analogue, octreotide(Drug information on octreotide) (Sandostatin); SNX-111, an N-channel calcium blocker; and midazolam(Drug information on midazolam) (Versed).[22,23]
Contraindications to the Use of Intraspinal Analgesics
Table 3 outlines the indications for intraspinal analgesia for patients suffering from intractable cancer-related pain syndromes. As noted, all patients who are candidates for intraspinal delivery of analgesics should have failed more conservative therapies. There should be no contraindications to implanting a drug delivery system and intrathecal catheter. These contraindications include allergy, localized infection in the areas where surgery is necessary, sepsis, and coagulopathy. When confronted with these possible contraindications in the dying patient in pain, physicians must weigh the possible risks of the procedure against the benefits and discuss these risks and benefits with the patient and family so that they can participate in the decision.
It is essential to establish opioid responsiveness to intraspinally administered opioids. There really is no magic to the concept of intraspinal delivery. If patients do not obtain any analgesia from systemic opioids, the use of intrathecal opioids is unlikely to work. In this situation, analgesia during an intraspinal opioid trial is most probably due to the nonspecific (placebo) effects of the drug.
The intraspinal route may still be valuable in such patients, however, because of the availability of nonopioid analgesics. In these cases, it may be best to consider epidural analgesia with opioids and/or bupivacaine(Drug information on bupivacaine) and/or clonidine. Epidural analgesia provides the sodium channel blockade of the peripheral and central nerves that may be necessary to achieve pain control. The addition of the opioid and/or clonidine delivers synergistic pain relief that allows for a reduction in the dose of all of the agents being used.
An intraspinal trial should evaluate analgesic and functional outcomes, rule out toxicity of the agent trialed, and mitigate against any nonspecific effects or placebo effects. Trials of intraspinal opioids and nonopioids alike have been performed by single-shot epidural administration or intrathecal placement of the drug or drugs, repeat single-shot epidural or intrathecal placement of the drug or drugs, and continuous drug delivery via the epidural or intrathecal route using an external pump.