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
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
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
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
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
(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 (Zecmil) or the
somatostatin analogue, octreotide (Sandostatin); SNX-111, an
N-channel calcium blocker; and 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 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.
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