Severe pain, independent of medical therapy, may cause sudden, unexpected death. Cardiac arrest is the cause, and practitioners need to know how to spot a high-risk patient.

Sudden, unexpected death may occur in a severe, chronic pain patient, and the terminal event may be unrelated to medical therapeutics. Fortunately, sudden death is not as commonly observed in pain patients as in past years most likely due to better access to at least some treatment. Sudden death still occurs, however, and practitioners need to know how to spot an “at-risk” patient.

Unexpected, sudden death due to severe pain is poorly appreciated, since many observers still view severe pain as a harmless nuisance rather than a potential physiologic calamity. In many cases, just prior to death, the patient informs their family that they feel more ill than usual and seek relief in their bed or on their couch. Unfortunately, some of these patients don’t awaken. Other patients die, without warning, in their sleep or are found collapsed on the floor. Modern medicine’s aggressive toxicology and forensic procedures after death have contributed to the poor understanding of pain’s death threat. In some cases, a pain patient that was being treated appropriately with an opioid or other agent with overdose or abuse potential has suddenly and unexpectedly died. Drugs were found in body fluids after death, and in my opinion a coroner wrongly declared the death to be an “accidental overdose” or “toxic reaction” to drugs rather than implicate the real culprit, which may have been an “out-of-control” pain flare.

This article is partially intended to call attention to the fact that the mere finding of abusable drugs at autopsy doesn’t necessarily mean that the drugs caused the death. In fact, the drugs may have postponed death. Some physicians have been falsely accused of causing deaths due to drug overtreatment when, in fact, undertreatment of pain may have caused the death. Additionally, opioid blood levels assessed at autopsy of a patient who died suddenly are all too often wrongfully considered accidental overdoses because the pathologist is unaware that chronic pain patients on a stable dose of opioids can be fully functional with serum levels of their prescribed opioids that far exceed lethal levels in opioid-naïve patients.1

Given here are the mechanisms of sudden, unexpected death in pain patients and some protective measures that practitioners must take to keep from being falsely accused of causing a sudden, unexpected death. More importantly, given here are some clinical tips to help identify the chronic pain patient who is at high risk of sudden, unexpected death so that more aggressive pain treatment can be rendered.

A Brief Anecdotal History

As a senior medical student at Kansas University in the early 1960s, I was required to take a rural preceptorship with a country doctor. In making our rounds one day to the county’s nursing home, I heard a farmer’s wife declare, “pain killed my mother last night.” Since then, I’ve repeatedly heard that pain killed a loved one. Folklore frequently mentions that people die “from,” as well as “in” pain. There is, however, little written detail of these events.

In the early years of my pain practice, which I began in 1975, I had several patients die suddenly and unexpectedly. This rarely happens to me today as I’ve learned to “expect the unexpected” and to identify which patients are at high risk of sudden death. In recent years, I’ve reviewed a number of litigation and malpractice cases of sudden, unexpected death in chronic pain patients. In some of these cases, physicians were accused of over- or misprescribing and causing a sudden, unexpected death, even though the patient had taken stabilized dosages of opioids and other drugs for extended periods. Also, the autopsy showed no evidence of pulmonary edema (a defining sign for overdose and respiratory depression). In cases where the physician was falsely accused, the post-death finding of abusable drugs in body fluids caused a family member, regulatory agency, or public attorney to falsely bring charges against a physician.

Setting and Cause

Unexpected deaths in chronic pain patients usually occur at home. Sometimes the death is in a hospital or detoxification center. The history of these patients is rather typical. Most are too ill to leave home and spend a lot of time in bed or on a couch. Death often occurs during sleep or when the patient gets up to go to the toilet. In some cases, the family reports the patient spent an extraordinary amount of time on the toilet just prior to collapse and death. Sudden and unexpected death, however, can occur anywhere at any time, as pain patients who have died unexpectedly and suddenly have been found at work or in a car.

Coronary spasm and/or cardiac arrhythmia leading to cardiac arrest or asystole is the apparent cause of death in the majority of these cases, since no consistent gross pathology has been found at autopsy.2-5 Instant cardiac arrest appears to account for sudden collapse or death during sleep. Perhaps constipation and straining to pass stool may be cardiac strain factors as some pain patients die during defecation. Acute sepsis due to adrenal failure and immune suppression may account for some sudden deaths.

Two Mechanisms of Cardiac Death

Severe pain is a horrific stress.6,7 Severe pain flares, acute or chronic, cause the hypothalamic-pituitary-adrenal axis to produce glucocorticoids (cortisol, pregnenolone) and catecholamines (adrenalin and noradrenalin) in an effort to biologically contain the stress.8,9 Catecholamines have a direct, potent stimulation effect on the cardiovascular system and severe tachycardia and hypertension result.10 Pulse rates may commonly rise to more than 100 beats per minute and even rise to more than 130 beats per minute. Blood pressure may reach more than 200 mmHg systolic and more than 120 mmHg diastolic. In addition to adrenal catecholamine release, pain flares cause overactivity of the autonomic, sympathetic nervous system, which add additional stimulation to catecholamine-induced tachycardia and hypertension. Physical signs of autonomic, sympathetic overactivity, in addition to tachycardia and hypertension, may include mydriasis (dilated pupil), sweating, vasoconstriction with cold extremities, hyperreflexia, hyperthermia, nausea, diarrhea, and vomiting.

The combined physiologic effects of excessive catecholamine release and autonomic, sympathetic discharge may put such strain on the heart to cause coronary spasm, cardiac arrhythmia, and sudden death.11 Pain patients who have underlying arteriosclerosis or other cardiac disease are at higher risk of sudden death. For example, a patient with angina or generalized arteriosclerosis is at high risk, and should be aggressively treated. Anecdotal reports have been made in which a patient whose pain was well controlled on opioids died unexpectedly with an underlying cardiac disease. In one report, a 40-year-old pain patient on opioids was found dead and the autopsy revealed previously unrecognized coronary artery disease, which was determined to be the cause of death. Some patient deaths may be due to other comorbid conditions, whether known or not known, and may not be related to the pain problem.

Case Example #1

A 60-year-old male with severe pain due to Lyme’s disease–related arthritis has generalized arteriosclerosis. When his pain flares, he has hypertension, tachycardia more than 100 beats per minute, and angina. On numerous occasions, he had been hospitalized for chest pain and he regularly requires nitrates for emergency coronary relief. He was treated with a long-acting opioid for baseline pain and a short-acting opioid for breakthrough pain. This regimen has controlled his angina and has prevented hospitalizations for more than 2 years.

The second mechanism, which may produce sudden death, is adrenal insufficiency. The hypothalamic-pituitary-adrenal axis may acutely and suddenly deplete during episodes of severe pain resulting in a life-threatening drop in cortisol, aldosterone, and possibly other adrenal hormones (Figure 1).12 With a precipitous drop in adrenal hormone production, there can be a severe electrolyte imbalance (eg, low sodium, high potassium), which may produce cardiac arrhythmia and death. Although undocumented, some sudden deaths may likely be a simultaneous result of excess sympathetic stimulation and electrolyte imbalance.

Identification of the At-risk Patient

An active, ambulatory pain patient who has mild to moderate, intermittent pain is not at high risk for sudden death. The patient at high risk for sudden death is a severe pain patient who is functionally impaired and has to take a variety of treatment agents, including opioids and neuropathic drugs, to control pain. In all likelihood, the patient who has centralized pain and who has central nervous system inflammation due to glial cell activation is the patient who will likely have flares severe enough to affect the endocrine and cardiovascular systems. Acute pain severe enough to cause cardiac overstimulation and death is usually only seen with severe trauma. Pain as a result of modern-day surgery is well controlled by analgesics, so perioperative sudden death due to surgically induced pain, per se, is essentially a thing of the past. Accidents, trauma, and war wounds are exceptions. In these situations, a patient in excruciating pain who shows signs of excess sympathetic discharge needs progressive emergency pain treatment to control excess sympathetic discharge.13,14 Excess sympathetic discharge signs that can be discerned at the bedside, emergency room, or accident site include mydriasis, diaphoresis, hyperthermia, tachycardia, hypertension, and hyperreflexia.15,16

The chronic pain patient who is at high risk for sudden death can usually be spotted at a clinical visit (Table 1). Patient and family will give a history of functional impairment. The most typical history will be one in which the patient will have constant, daily pain intermixed with severe flares, which cause a bed or couch-bound state. Even though medication dosages may be high, they may not be effective enough to prevent pain flares and sudden death. The patient will likely demonstrate excess sympathetic discharge. By history, this includes waves or episodes of allodynia, hot and cold flashes, hyperalgesia, and severe insomnia. Physical exam may reveal excess sympathetic discharge by any or all of the following signs: tachycardia, hypertension, vasoconstriction (cold hands/feet), mydriasis (dilated pupil), and hyperreflexia.

Cortisol, pregnenolone, or corticotropin (adrenocorticotropic hormone) serum levels may be subnormal indicating that the immune and healing systems are impaired, leaving the patient subject to infections and interference with opioid effectiveness.

When high-risk indicators are found, therapeutic adjustments in type, quantity, and quality of pain treatment must be implemented to minimize or eliminate risk factors. In particular, there should be attempts to normalize hypertension, tachycardia, and hormone levels.

Methadone Administration And Sudden Death

Other than overdose and respiratory depression, the opioid methadone has been associated with a cardiac conduction defect (prolonged QT interval) called “torsades de pointes,” which may cause an unexpected, sudden death.17,18This defect may cause sudden death by cardiac arrests. No other opioid has been credibly associated with cardiac conduction defects. In addition to the problem of QT prolongation, many methadone-related deaths occur during the first few days of use, making the deaths in these instances more likely due to the prescriber’s unawareness of methadone’s long half-life and, therefore, accumulation in the bloodstream because the dose was titrated too quickly.

However, the recognition of QT prolongation has caused considerable controversy and many experts believe that an electrocardiogram should be done to screen for a prolonged QT interval before and/or during methadone administration.17 The occurrence of “torsades de pointes” with methadone is usually dose related and associated with concomitant use of antidepressants or benzodiazepines. If a patient who takes methadone suddenly dies due to cardiac arrhythmia, there will be no gross pathology at autopsy, which is typical of sudden death in a pain patient. The prescribing physician may, however, be accused of overprescribing methadone. Due to this risk, many physicians have made a choice to shun methadone and avoid the risk of being falsely accused for overprescribing. From a clinical perspective, the use of antidepressants and benzodiazepines should be restricted if methadone is prescribed, since these ancillary agents appear to facilitate methadone deaths.

Risk of Sepsis

Although not well documented, acute sepsis and sudden death probably occur in some severe, chronic pain patients. The mechanism is probably initiated by subnormal serum levels of cortisol or other hormones due to adrenal depletion. Chronic subnormal adrenal hormone levels severely compromise the protective immune system in the body, rendering the patient susceptible to virulent bacteria and other pathogens.19,20 The author has frequently found extremely low levels of cortisol (fewer than 1.0 mg/dL) in undertreated intractable pain patients. One can only wonder as to how many pain patients have suddenly died from acute sepsis. Although documentation of this pathologic event is scant, practitioners should be aware that extremely low serum levels of adrenal hormones are known to be associated with a compromised immune system and sepsis.

Death Following Sudden Opioid Cessation

There is the misguided notion among some addiction and mental health practitioners that withdrawal from opioids is an innocuous procedure that is risk free. This school of thought says that only withdrawal from alcohol and benzodiazepines is risky. This is generally true unless the patient who is dependent upon opioids has severe underlying pain and is taking opioids solely for pain control. In some patients, opioids may mask underlying pain so well that a practitioner may not even believe that pain recrudescence is a possibility once opioids are stopped.

Patients who have severe pain that is well controlled by opioids may be sudden-death candidates if their opioids are precipitously stopped. If opioids in a severe pain patient are precipitously stopped, the masked pain may flare causing severe autonomic, sympathetic discharge and overstimulation of the adrenals to produce excess catecholamines with subsequent cardiac arrhythmia and arrest. Malpractice suits have occurred when opioids have been precipitously stopped in a pain patient. Here are two examples known to the author.

Case Example #1

A 45-year-old woman with fibromyalgia and severe pain was well controlled with extended release morphine for baseline pain and short-acting hydrocodone for breakthrough pain. She entered an in-patient detoxification program where she was told that fibromyalgia only required psychotherapy and no opioids. The detoxification program precipitously stopped all her opioids and placed her in isolation for punishment because she was using opioids as a “crutch” rather than “facing her problems.” She died suddenly about 36 hours after all opioids were stopped.

Case Example #2

A 42-year-old male had a work injury and subsequently suffered reflex sympathetic dystrophy (RSD) or complex regional pain syndrome (CRPS). His pain was reasonably well controlled with fentanyl transdermal patches (Duragesic) for baseline pain and short-acting oxycodone (OxyContin) for breakthrough pain. His workers’ compensation carrier had him evaluated by “experts” who claimed that pain couldn’t possibly exist for more than about 6 months after injury, and RSD and CRPS were not “legitimate diagnoses.” His workers’ compensation carrier, based on their “experts’” opinions, precipitously stopped all his opioids by refusing to pay for them. The man died suddenly 4 days after abrupt cessation of his opioids.

Value of Opioid Serum Levels

Patients who have severe chronic pain, take opioids, and demonstrate some high-risk signs and symptoms for sudden death as described above should have opioid blood levels done. Why? Legal protection. If a severe chronic pain patient who takes opioids suddenly dies, the practitioner may be accused of overprescribing and causing an overdose death unless he/she has pre-death opioid blood levels on the patient’s chart. Keep in mind that there will be no gross cardiac pathology at autopsy if the patient suddenly dies of a cardiac arrhythmia or arrest. And, the coroner will likely call the death a drug overdose and blame the prescribing physician. Here are two illustrative cases.

Case Example #1

A 28-year-old male, former football player had severe spine and knee degeneration. He died in his sleep and his death was brought under investigation by the coroner. At autopsy he had a methadone blood level of 400 ng/mL. The prescribing physician was about to be charged with negligence by the local district attorney, until the physician showed that, in life, the patient’s methadone blood levels ran between 500 to 650 ng/mL.

Case Example #2

A 58-year-old female with genetic porphyria had suffered from severe generalized pain for more than 20 years. She collapsed in her living room in sudden death. At autopsy she was found to be wearing three fentanyl dermal patches (100 mcg/hour). At autopsy she demonstrated a fentanyl blood level of 10 ng/mL and a morphine blood level of 150 ng/mL. Her prescribing physician was able to show the sheriff’s investigators that in pre-death treatment, she had fentanyl and morphine blood levels considerably above these found at autopsy. No charges were ever brought against the physician.

Summary

Although sudden, unexpected death in chronic pain patients appears to be declining in incidence due to greater access to treatment, practitioners need to be aware that sudden, unexpected death may occur independent of opioid administration. The precise mechanism of death is cardiac arrest or asystole due to coronary spasm, arrhythmia, and/or electrolyte imbalance. Severe chronic pain produces excess sympathetic discharge through the autonomic nervous system and overstimulation of the hypothalamic-pituitary-adrenal axis, which causes great output of adrenal catecholamines. The chronic pain patient who is at highest risk for sudden death is the patient whose uncontrolled pain and pain flares are so great as to cause a high degree of functional disability. Those pain patients who are ambulatory and active are not at high risk for sudden death. The attainment of opioid blood levels during treatment of patients who are at high risk for sudden death are advised as a medical-legal protection should opioids be present in blood after death. Patients who are identified as high risk should be monitored by regular clinic visits, and efforts should be done to control excess sympathetic discharge and adrenal deficiencies.