Analgesic Pathways

Many analgesic pathways interfere with pain transmission within the brain or spinal cord. Several pathways that originate in the frontal lobe and hypothalamus terminate in the gray matter surrounding the third ventricle and aqueduct of Sylvius (periaqueductal gray matter). They contain large amounts of endogenous opioids, which are powerful analgesics (Box 14-1). Implanted electrodes that stimulate the periaqueductal gray matter area may provoke the release of endogenous opioids and thereby induce profound analgesia.

Box 14-1

Glossary

β-endorphin: An endogenous opioid concentrated in the pituitary gland and secreted with ACTH. It consists of amino acid numbers 61–91 of β-lipotropin and gives rise to the enkephalins (see Fig. 14-2)

β-lipotropin: A 91-amino-acid polypeptide, which may be an ACTH fragment. It gives rise to β-endorphin but has no opioid activity itself (that is, β-lipotropin is not an endogenous opioid)

Dynorphin: An endogenous peptide opioid that binds to kappa opioid receptors

Endogenous opioids: Polypeptides (amino acid chains) found within the central nervous system that create effects similar to those of morphine and other opioids. The effects of both endogenous and exogenous opioids are characteristically reversed by naloxone

Endorphins: Endogenous morphine-like substances or opioid peptides. This term is virtually synonymous with endogenous opioids

Enkephalins: Short (5-amino-acid) polypeptide endogenous opioids that include met-enkephalin and leu-enkephalin. They are found primarily in the amygdala, brainstem, and dorsal horn of the spinal cord

Naloxone (Narcan): A pure opioid antagonist that reverses the effects of endogenous and exogenous opioids

Substance P: An 11-amino-acid polypeptide that is probably the primary pain neurotransmitter at the first synapse of the primary afferent neuron in the spinal cord

ACTH, adrenocorticotropic hormone.

Analgesic pathways also originate in the brainstem and descend in the spinal cord’s dorsolateral funiculus. They provide “descending analgesia” relief of pain by inhibiting both spinal cord synapses and their ascending pathways. Unlike most other analgesic pathways, they release serotonin.

Endogenous Opioids

Often called endorphins (endogenous morphine-like substances), endogenous opioids – endorphins, enkephalins, and dynorphins – are powerful analgesic, amino-acid chains (polypeptides) synthesized in the CNS (Fig. 14-2). Endogenous opioids bind to receptors in the limbic system, periaqueductal gray matter, dorsal horn of the spinal cord, and other CNS sites. Neurologists commonly say that a “runner’s high” and the initial painlessness reported by wounded soldiers serve as examples of endorphins’ analgesic effects.

FIGURE 14-2 Endogenous opioids are synthesized and secreted, along with adrenocorticotropic hormone (ACTH), from the pituitary gland in times of stress or acute pain. A large precursor molecule (not pictured) gives rise to ACTH and β-lipotropin, which are often released together. β-lipotropin gives rise to β-endorphin and met-enkephalin, but another precursor gives rise to leu-enkephalin. (The asterisks denote the important endogenous opioids, and the numbers within parentheses are the amino acid units in the polypeptide chains.)

Synthetic (exogenous) opioids, particularly morphine and other medicines, are virtually identical to endogenous opioids. They bind to the same CNS receptors and produce the same effects – analgesia, mood elevation (euphoria), sedation, and respiratory depression. Naloxone (Narcan), an antagonist that competitively binds to the opiate receptor, reverses the effects of endogenous, as well as exogenous, opioids. Indeed, naloxone’s opioid antagonist effect is so characteristic that naloxone-reversibility serves as a criterion for ascertaining that opioid pathways mediate an analgesic’s effect.

Treatments

Physicians prescribe numerous medications and administer them through various routes. Some alleviate pain by reducing tissue damage, interrupting pain transmission through peripheral or central pathways, or blunting its impact on cerebral structures. The addition of psychologic treatment and physical therapy may further reduce pain and, as part of a complete care plan, decrease suffering, restore activities of daily living, and return control to patients. Because chronic pain remains notoriously refractory to conventional treatment, neurologists aim for pain management, not pain cure.

Nonopioid Analgesics

As previously mentioned, aspirin, other salicylates, NSAIDs, steroids, and acetaminophen – nonopioid analgesics – inhibit prostaglandin synthesis at the injury (Box 14-2). Through this mechanism, these medicines relieve acute and chronic pain of mild to moderate severity.

Nonopioid analgesics generally provide steady analgesia for weeks to months and avoid several potential problems. In particular, after completing a course of treatment, patients do not experience withdrawal symptoms. Also, except for high-dose steroids potentially causing steroid psychosis (see Chapter 15), these analgesics do not induce mood, cognitive, or thought disorders.

On the other hand, large doses of NSAIDs and aspirin cause gastric irritation or hemorrhage, and prolonged use increases the risk of cardiovascular disease. In addition, although nonopioid analgesics provide dose-dependent pain relief, they do so only up to a point. Once these medicines provide their maximum pain relief, greater doses do not increase their benefit – the “ceiling effect.”

Nonopioid analgesics are more effective if patients take them on a prophylactic basis. For example, taking nonopioid analgesics prior to dental procedures or menses will avert much of the pain. They are also more effective if taken in a generous initial “loading” dose.

Although nonopioid analgesics alone offer minimal benefit in cases of neuropathic pain, they act synergistically when taken in combination with opioids. In other words, peripherally acting nonopioid analgesics enhance centrally acting opioid analgesics. For example, adding NSAIDs to morphine helps alleviate the pain of metastases to bone. Because nonopioid analgesics allow a smaller dose of opioids to be effective, they have an “opioid-sparing effect.”

With routine use, acetaminophen by itself or as an enhancement to opioids provides effective, reasonable safe analgesia. Stern warnings about acetaminophen compounds, such as oxycodone-acetaminophen (Percocet) and hydrocodone-acetaminophen (Vicodin), as well as acetaminophen itself, causing permanent liver damage are justifiable, but usually when looking at the aftermath of an overdose or their use by alcoholic individuals.

Opioids

When chronic pain results from cancer, neurologists categorize it as “cancer” or “malignant” pain, but when it results from other conditions, “noncancer” pain. Opioids are unquestionably indicated for cancer pain (see Box 14-2). In addition, a number of studies suggest that they are indicated for chronic noncancer pain syndromes.

Opioids have no ceiling effect. Greater doses or more potent preparations increase their analgesic effect. Adding NSAIDs or other nonopioid analgesics enhances opioids’ effect without risking their side effects. On the other hand, when treating patients with noncancer pain who do not find relief with opioid treatment, physicians should slowly discontinue opioids rather than increasing the dosage.

Chronic pain patients may obtain opioid treatment from transdermal patches, intranasal sprays, rectal suppositories, and epidural injections. A particularly innovative technique, patient-controlled analgesia (PCA), allows patients to regulate continual or intermittent intravenous opioid infusions. Through controls in the system, patients regulate the depth of analgesia without causing respiratory depression. Even 6-year-old children can safely and effectively administer PCA.

Compared to older opioids, newer ones provide more rapid onset and longer duration of action. Some are long-acting because they are embedded in a matrix that slowly releases its medication.

Administering opioids by PCA, patches, or long-acting oral preparations on a regular prophylactic or time-dependent basis, such as every 2–4 hours, is more effective than administering them only at the onset of pain. By administering opioids only after pain has developed makes it more difficult to control, creates a pattern of “hills and valleys” (first undertreatment and then overtreatment), prevents a restful sleep, and increases side effects. Moreover, because patients, fearful about pain recurrence, develop anxiety and preoccupation with obtaining their medicines, they may seem to behave as addicts (see later).

Physicians who prescribe narcotics should select long-acting preparations, such as methadone or a transdermal opioid. Also, because various opioids affect different regions of the mu (µ) and related receptors, physicians should vary the opioid for patients with intractable pain. Transdermal and extended-release oral opioid formulations carry a disproportionately great risk of morbidity and mortality.

Physicians should also avoid changing from oral to parenteral forms of opioid at a given dose because the substitution will likely lead to an overdose. In the reverse situation, changing the same dose from an intramuscular or intravenous injection to pills is likely to produce undertreatment, which would cause withdrawal symptoms and recurrence of pain.

In an attempt to control indiscriminate prescription of opioids, the Food and Drug Administration will soon launch Risk Evaluation and Mitigation Strategies (REMS) for physicians who prescribe opioids. REMS will hopefully reduce inappropriate prescriptions, abuse, overdose, and other untoward effects.

“Addiction”

In a situation akin to drug addicts, within weeks of beginning opioid treatment, patients require increasingly greater quantities to produce the same level of anesthesia (tolerance) as opioids desensitize receptors. Similarly, abruptly stopping opioid treatment produces unpleasant symptoms (withdrawal). However, because the two situations differ in several important respects, physicians certainly do not label a terminal cancer patient who requires opioids a drug addict.

Although tolerance and withdrawal characterize physical dependence, physicians in pain management services, as ones in psychiatry, define addiction primarily in behavioral terms, such as potentially harmful drug-seeking activity and overwhelming involvement with use of a drug. They consider tolerance and dependence, which often occur together but can occur independently, as physiologic responses, an expectable aspect of medical treatment, and not peculiar to opioids. They also note that inadequate treatment and development of tolerance drive pain patients to be overly concerned about their opioid schedule and to seek larger doses. Physicians unfamiliar with pain management may interpret this behavior as “drug-seeking” and an indication of addiction, but many pain management physicians consider it iatrogenic pseudoaddiction. On the other hand, some pain management physicians remain skeptical and consider pseudoaddiction to be true addiction.

Moreover, pain management physicians quip that other physicians’ fear of creating addiction has led to the most common side effect of opioid treatment, undertreatment. In fact, addiction rarely develops in previously opioid-naive individuals who develop an acute painful illness that requires opioids for several weeks. Pain management physicians have been advocating continual opioid treatment of moderate to severe noncancer as well as cancer pain.

Other Opioid Side Effects

For the psychiatric consultant, a dilemma is the similarity of opioid-induced mental status changes to those induced by head trauma, metabolic aberrations, and cerebral metastases. Because opioids may cause delirium and depress the level of consciousness, which would obscure the clinical picture, neurologists and neurosurgeons avoid treating head trauma patients with opioids.

Another opioid side effect, hypoventilation – slow and shallow breathing – represents its primary life-threatening one. However, in practical terms, administering opioids to patients with pulmonary disease, rather than an overdose, is the usual cause of hypoventilation. Also, patients develop tolerance to hypoventilation along with their other side effects.

Although depression of sensorium and hypoventilation loom large to physicians as major iatrogenic problems, constipation remains the most troublesome side effect for patients. Rather than trying to reverse this inevitable complication, physicians can prevent it by ordering a combination of laxatives, such as senna (Senokot), and stool softeners, such as docusate sodium (Colace). They can also prescribe an oral, selective mu-opioid receptor antagonist that does not cross the blood–brain barrier, such as alvimopan (Entereg).

To prevent or alleviate opioid-related nausea, physicians should prescribe antiemetics, but they should cautiously prescribe antiemetics containing phenothiazine or other dopamine-blocking agent because they can cause dystonic reactions or parkinsonism (see Chapter 18). In another caveat, pharmacologic marijuana, such as dronabinol (Marinol) and nabilone (Cesamet), generally reduces nausea, pain, and anxiety; however, robust formal studies have not established that they are the most effective treatment when cancer or chemotherapy has been responsible for these symptoms. Moreover, they may cause transient mood and thought disorders.

The use of specific opioids is fraught with difficulties. For example, phenytoin and carbamazepine – whether prescribed for their antiepileptic activity, mood modulation, or pain control – accelerate methadone metabolism. Therefore, giving either of these AEDs to patients on methadone maintenance may precipitate withdrawal symptoms. To avoid that problem, physicians should increase the methadone dose when they add those medications.

Heroin, a problematic opioid, is no more effective in relieving pain or improving mood than morphine, but its potential for abuse is much greater. Regardless of several medical and nonmedical groups’ assertions, heroin has no legitimate use that cannot be better fulfilled by the current array of medicines.

As with other medicines, physicians should discontinue opioids when unnecessary. Rather than abruptly stopping opioids, which would probably lead to withdrawal, physicians might use an exit strategy of tapering opioids by reducing their dose by 50% every 3 days. Alternatively, physicians might briefly replace a short-acting opioid, such as morphine, with a long-acting one, such as methadone, and then prescribe a nonopioid analgesic. If withdrawal still complicates the process, benzodiazepines may alleviate the physical or mental discomfort, and clonidine (Catapres) may blunt autonomic nervous system hyperactivity (see Chapter 21).

Chronic Opioid Therapy Debate

Over the past decade, neurologists, pain management specialists, and other physicians began to prescribe long-term opioid treatment for many noncancer conditions, including osteoarthritis, headache, postoperative low back pain, and fibromyalgia. These physicians offer several arguments that have gained increased acceptance. They claim that, when used to control otherwise intractable pain, opioids are not addictive; opioids are effective, safe, and allow patients to work, use machinery, and drive; and, more than other medicines, opioids increase function, reduce suffering, and restore sleep.

Physicians prescribing chronic opioid therapy expect patients to agree, often with a written contract, to use only the opioid in preset amounts and only from a single physician. Patients must also give permission for random urine testing for illicit substances, particularly drugs of abuse. Physicians monitor patients’ social and occupational functioning as well as their pain and urine tests.

Physicians who have opposed expanding opioid prescription offer several counterarguments. Opioids reduce pain less than 2–3 points on a 0–10 scale. Chronic opioid therapy may be counterproductive in several conditions. It portends worse long-term outcomes for headache and low back pain, and tends to convert episodic migraines or tension-type headache to persistent daily headache (see Chapter 9). Patients demand opioids when less potent or alternative measures, even nonpharmacologic ones, would suffice. In addition, patients may subvert medical treatment. They may seek opioids for their euphoric effect rather than for pain relief. Falsely reporting the persistence and severity of pain to obtain opioids, patients prolong their disability. Some patients, claiming intractable pain, demand excessive quantities, but sell or pass along their opioids. To avoid this “diversion” of opioids, some physicians go so far as to ask the patient who has been prescribed fentanyl patches to return the used ones, which should have the patient’s hair stuck to the patch’s adhesive. Some patients use opioids to tide them over an addiction to illicit drugs. For many patients, obtaining opioids takes over their day-to-day concerns.

Some neurologists feel that chronic opioid therapy is rife with misuse. Examples include using other alcohol and illicit substances in addition to the opioids, selling or trading the opioids, and surreptitiously obtaining additional quantities of opioids. Risk factors for misuse are family as well as a personal history of substance abuse; age 16–45 years; presence of a “psychiatric condition,” which includes schizophrenic disorders, affective psychosis, neurotic disorders, and personality disorders; and, in women, preadolescent sexual abuse. Rates of misuse of opioids among chronic opioid therapy patients range from 3% to 30%.

Long-term opioid treatment, especially at high dosage or following a dose increase, generally produces sedation, impairs cognition, and interferes with psychosocial function. In addition to leading to these neuropsychologic effects, it leads to the usual opioid side effects, particularly chronic constipation and hypogonadism.

Finally, physicians prescribing opioids are subject to administrative oversight that may be stringent and punitive. Both state and federal investigators pursue possible irregularities.