Diagnosis and treatment of opiate-resistant pain in advanced AIDS

A 35-year-old man with AIDS [acquired immunodeficiency syndrome] was admitted for end-of-life care. He had tested positive for the human immunodeficiency virus (HIV) in 1986, when he was diagnosed with Pneumocystis carinii pneumonia. He subsequently developed non-Hodgkin's lymphoma with involvement of abdominal and periaortic lymph nodes. He had responded initially to antiretroviral therapy and chemotherapy, although his CD₄ cell count never rose above 100 × 10⁶/L (100/μL), indicating ongoing severe immune deficiency. He had stopped HIV therapy because of side effects 1 year before admission, and lymphoma had progressed. At the time of admission, he had severe neuropathic leg and abdominal pain with partial bowel obstruction from the lymphoma. Symptoms had made care at home (rendered by his mother and partner) very difficult, even though both were intensive care unit nurses.

On admission, the patient was receiving patient-controlled-analgesia (PCA) morphine sulfate through a subclavian central line at an already high rate of 90 mg-per hour with the ability to self- or partner-deliver 30 mg every 6 minutes. This was completely ineffective in managing his pain. The patient was remarkably responsive and coherent, even though narcotic hallucinosis (visual and auditory hallucinations) was intermittently present. The baseline dose of morphine was dramatically increased during the first 48 hours to 620 mg per hour; this brought no change in pain relief but worsening of his hallucinosis.

THE CLINICAL QUESTIONS

In this case, the patient continued to have pain despite enormous doses of opiates. This raises a number of clinical questions: How common is pain in patients with AIDS? What is opiate-resistant pain? Why do patients vary in their responses to opioids? What conditions does opiate-resistant pain occur in? How is it recognized? Are particular patients at high risk of developing it? How is opiate-resistant pain treated?

SEARCHING THE LITERATURE

We searched MEDLINE for articles on pain in AIDS, using the search terms AIDS, pain, and opiates. We included English-language articles from 1985 to 2000 that were trials or reviews.

How common is pain in AIDS?

Despite aggressive management of HIV infection or AIDS in the United States, pain remains a major component of the illness. Estimates of the prevalence of pain in patients with AIDS range from 40% to 93%.^1,2,3 Frich and Borgbjerg enrolled 95 patients with AIDS in a prospective longitudinal study for a 2-year period and found that the overall incidence of pain was 88% (84 patients), with 66 patients (69%) in moderate to severe constant pain.³ In Singer et al's study of 191 outpatients with HIV infection, 53 (28%) complained of pain.⁴ Despite the high frequency of pain in patients with HIV infection or AIDS, pain relief is often overlooked in the management of this disease.^5,6,7,8,9,10 Because AIDS is a diverse disease with many presentations, pain location and quality of pain vary greatly among patients. The most common sites of pain in AIDS are the extremities (peripheral neuropathy or joint pain), followed by the head, gastrointestinal tract, genitalia (usually herpetic pain), and back.^2,3,9,10 A substantial fraction of patients have more than one pain complaint.² Pain is, therefore, extremely common and multifaceted in patients with AIDS, and pain syndromes vary considerably in intensity and locale.

What is opiate-resistant pain?

Simply put, opiate-resistant pain is pain that is apparently completely unresponsive to the administration of large doses of opiate narcotics. Authors use many different names for pain that is not relieved by opioids (see box). This phenomenon should be distinguished from pain that is due to inadequate dosing with opiates. We define further some of the terms used to describe pain that is unrelieved by opioids.

Table 1.

Phrases commonly used for pain not relieved by opioids
Opioid poorly responsive pain11 Paradoxical pain11,12,13 Overwhelming pain syndrome13 Opioid-nonresponsive pain14 Pseudo-opioid-resistant pain14 Opioid-irrelevant pain14 Overmorphinization14 Opioid-resistant, recalcitrant pain15

Pseudo-opioid-resistant pain

Evers defined pseudo-opioid-resistant pain as pain that persists, despite appropriate opiate dosing, due to poor communication of pain experience between providers and patients, the improper administration of opiates, or the refusal by the patient or family to accept treatment choice with opiates.¹⁵

Overmorphinization

Side effects of morphine include hallucinations (as in the case in this review), confusion, headache, nausea, flushing, agitation, and dysphoria.¹⁶ In a patient with a decreased level of consciousness, these effects may be confused with pain behavior itself. This has been called overmorphinization.¹⁴

Opiate-irrelevant pain

Opiate-irrelevant pain has been defined as complaints of pain that are more a reflection of social, psychological, or spiritual turmoil than a result of physical injury or damage.¹⁷

Why do patients vary in their response to opioids?

Variation in response to opioids has been suggested as a mechanism for pain that is resistant to opioids. Pain responses to morphine vary based on previous exposure to opioids, simple variation between people, the type of pain, and patients' sex (men and women respond differently to opiates).^18,19 Individuals have different side effect profiles and analgesia from different opiates, even when the drugs selected work with similar mechanisms.^20,21 Genetic factors have also been postulated to determine opioid responsiveness,²¹ and responsiveness varies with mode and frequency of delivery. The prevailing clinical recommendation is that opioid dose should always be titrated until observed effects occur based on patients' responses.²¹ When this recommendation is followed aggressively, resistant pain is clearly more than just inadequate dosing, as the case described here illustrates.

What medical conditions does opiate-resistant pain occur in?

Opioid-resistant pain has been noted in the literature in many conditions besides AIDS—cancer, chronic pain, neuropathy, complex regional pain syndrome (a combination of neuropathic and musculoskeletal pain), central pain, postherpetic neuralgia, and pancreatitis.²¹ It is estimated that 20% of cancer patients do not respond well to traditional opioid pain management.¹¹ However, there has been little examination of the existence or prevalence of opioid-resistant pain in patients with AIDS. In 1994, Anand et al studied 24 AIDS patients who had severe chronic refractory pain⁵; they found that pain generally could be relieved by the use of round-the-clock (as opposed to “as needed”) dosing and careful follow-up, regardless of substance abuse history.

In previous studies of intractable pain near the end of life among persons with AIDS, low rates of opiate resistance were found; fortunately, cases like the one described here are rare. Among 186 patients with AIDS who were receiving home hospice care, 2 (1.1%) were noted to have ongoing pain, despite as much as 100 mg-per-hour morphine drip.¹ In another study, 226 patients with AIDS were admitted to a special AIDS facility for terminal care (out of 740 total admissions for AIDS during this period); 109 used PCA for pain control.²² Of the 226, 12 of the terminal AIDS patients (5%) (11% of PCA users, 1.6% of all admissions) had opiate-resistant pain. As in a previous study,⁵ no association with a history of drug abuse was found.

How is opiate-resistant pain recognized?

In the absence of a clear pathophysiologic mechanism for opiate-resistant pain, simple clinical criteria have been developed (see next box).²² Opiate-resistant patients are generally receiving PCA morphine intravenously (IV) at a dosage of at least 100 mg an hour (or an equivalent dose of another opiate) and have persistently high pain ratings, even after the dose of medication is doubled. Changing the route of administration (eg, from IV to epidural) or to a different opiate does not make any difference in the level of pain relief.,

Table 2.

Clinical criteria for opiate-resistant pain22
Morphine sulfate has been administered in a dosage of at least 100 mg an hour (or equivalent IV dosing of another opiate) The patient has not had relief of pain, as evidenced by persistently high pain ratings Pain persists even after the already-high dose of medication is doubled

Table 3.

Treating opiate-resistant pain: adjuvant agents to use with opiates for pain relief17
Anticonvulsants (eg, phenytoin, carbamazepine, barbiturates, gabapentin) Antidepressants (tricyclic antidepressant agents, selective serotonin-reuptake inhibitors) Antihistamines (eg, diphenhydramine, hydroxyzine) Steroids (eg, dexamethasone, prednisone) Nonsteroidal anti-inflammatory agents (eg, acetaminophen, ibuprofen) Psychotropic neuroleptic agents (eg, haloperidol)

Anand and colleagues contend that with proper opiate dosing and round-the-clock administration, relief from opiate-resistant pain can almost always be achieved.⁵ However, their study was likely too small to contain an opiate-resistant patient, given the rarity of this phenomenon—patients in their study likely had recalcitrant pain, rather than opiate-resistant pain. In case studies of patients with opiate-resistant pain, the patients do not respond to any opiate at all.^{22,23,24,25,26}

Are there particular patients who are at high risk of developing opiate-resistant pain?

No distinguishing characteristics of patients who might be at risk of opiate-resistant pain have been identified. In particular, no obvious association has been found between opioid-resistant pain and psychological distress or depression, neuropathy, or injection drug use.

In patients with cancer, psychological distress and affective disturbances affect the experience of pain and an individual's response to opioid medication.^21,23 This is not true of opiate-resistant pain, however. The pain experience is due to psychological turmoil, not to the stimulation of pain receptors from a physical cause—in other words, it is opioid-irrelevant pain.¹⁷

Neuropathic pain syndromes, including postherpetic neuralgia and peripheral neuropathy, which are commonly known to cause a decreased responsiveness to opioids,^21,24 occur in 15% to 50% of patients with AIDS. But again, the pain in these syndromes is not true opiate-resistant pain. Instead, it is due to neurotoxicity from antiviral medications, neurotoxicity from HIV itself, autoimmune processes, coinfections (eg, cytomegalovirus), and nutritional factors.²⁵

In discussions about opioid-resistant pain, inevitably the question is asked whether it can occur as a result of opioid tolerance in patients with a history of long-term prescribed opiate use or of abuse of heroin or other illicit opiates. In the rare cases of opioid-resistant pain reported in the literature, continued pain despite astronomic doses is evident. Based on our review of the literature, in these patients, opiate tolerance is not the primary issue underlying the lack of pain relief. A history of injection drug abuse or long-term opiate use is not a risk factor for the development of opiate-resistant pain,^5,22 which suggests that tolerance is not an underlying mechanism for this kind of pain.

How is opiate-resistant pain treated?

Once recognized (using the clinical criteria described earlier), opiate-resistant pain can be treated effectively with the use of adjuvant agents. Treatment must be aggressive, swift, and multidisciplinary and rely on good communication among nurses, primary care physicians, and consultants such as anesthesiologists and pain specialists. The treatment is based on continuing the opiate medication but adding adjuvant medications that have a synergistic effect with the opiate to provide pain and anxiety relief (see next box).²⁷

When patients have extremely high levels of uncontrolled discomfort, as in the case described here, the use of phenobarbital and other psychotropic medications can be effective.²⁷ The half-life of phenobarbital is several days; the implication of this long half-life is that an IV drip is rarely necessary (as opposed to morphine, which has a half-life of 1-2 hours). Anticonvulsant dosing of phenobarbital is indicated, with a loading dose of 20 mg/kg (1-1.5 g) given slowly IV in 200-mg increments each over an hour and repeated every few hours until loading is achieved. After loading, subsequent doses of 100 to 200 mg per day are almost always adequate; leeway can be provided to experienced staff by providing orders for 100 to 200 mg every 4 hours as needed for pain, rigidity, or seizures. Alternatively, the neuroleptic haloperidol can be used in dosages of 2 to 10 mg every 2 to 4 hours as needed. It is important to know that low doses (30-60 mg) of phenobarbital can actually increase pain sensation, and paradoxical excitement can occur; so phenobarbital should be given in anticonvulsant doses. Opiate-resistant pain can arise in any terminal illness, including cancers, and adjuvant drugs like neuroleptic agents and barbiturates have been as useful in these patients as in patients with AIDS.²⁷

Because our patient continued to suffer while receiving very high doses of narcotics despite a rapid escalation of dosing, he met clinical criteria for opiate-resistant pain.²² The evidence in pain management literature suggests that the best way to manage this pain is by a liberal use of adjuvant therapy.^7,24,27 Therefore, several agents were added: dexamethasone, 4 mg every 6 hours; hydroxyzine hydrochloride, 25 mg every 6 hours; nortriptyline hydrochloride, 50 mg every 12 hours; and liberal doses of benzodiazepines (diazepam and lorazepam). At this point, a consulting anesthesiologist inserted an epidural catheter with morphine infusion, which was effective in pain relief, and the patient was comfortable for the ensuing 3 days. After this respite, the pain unfortunately returned, even with escalation of the epidural dosing. IV morphine was reinstituted at 1,500 mg per hour with no relief, and this was then changed to hydromorphone hydrochloride, 500 mg per hour, with no improvement. At day 7, the patient remained responsive but clearly in severe, ongoing pain in the abdomen and legs. The anesthesiologist and internist, in consultation with the patient and family, added phenobarbital, with a loading dose of 200 mg every 4 hours for 4 doses, then 200 mg a day, each dose given slowly over 1 hour. This made the patient sleepy, but it relieved his pain completely after the second dose. The patient lived another 48 hours on this regimen and died comfortably on day 9.

CONCLUSIONS

Although pain is common in patients with advanced AIDS, opiate-resistant pain is not. No distinguishing characteristics of patients who might be at risk of opiate-resistant pain have been identified. There is no obvious association between opioid-resistant pain and depression, injection drug use, or neuropathy. Health care professionals must be attentive to pain and symptom assessment and communication about pain and pain treatment. Good palliative care requires staff to use all of their medical and communication skills—careful assessment (using pain and sedation scales), attention to psychosocial needs of the patient and family, attention to side effects, and highly individualized therapeutic regimens that should be reassessed and altered frequently based on patients' responses.

Summary points

• Opiate-resistant pain is pain that appears to be completely resistant to opiates

• Opiate-resistant pain is rare and occurs in patients with AIDS, cancer, peripheral neuropathy (including postherpetic neuralgia), and pancreatitis

• A patient who remains in pain while receiving hundreds of milligrams of opiates and who has no discernable response to doubling of the dose has opiate-resistant pain

• Opiate-resistant pain can be effectively treated by the aggressive use of adjuvant agents such as barbiturates and neuroleptic medications

Figure 1.

Haloperidol, shown in this color micrograph, is helpful in treating severe opiate-resistant pain

Michael Davidson/Florida State University