Addiction

The likelihood of a patient developing addictive disease as a result of being treated with opioids has already been discussed in Chapter 11. The risk of iatrogenic addiction after short-term exposure for postoperative pain is known to be less than 1%. The risk during long-term treatment is not clear, and is likely to be related to risk factors, the most important of which—a personal history of drug or alcohol abuse, or a family history of drug or alcohol abuse—underscore the importance of a genetic determinant for the disease of addiction.

A review of definitions related to conditions often confused with addiction will clarify some of the confusion about addiction. Following are the definitions proposed by the American Academy of Pain Medicine (AAPM), the APS, and the American Society of Addiction Medicine (ASAM) (2001):

In addressing the relationship between addictive disease and the use of opioids for persistent noncancer pain, the following two questions need to be considered:

Very few studies have been conducted to examine the latter question. The appropriate research needs to start with patients who do not already have addictive disease and find out how many become addicted as a result of long-term use of opioids for pain. In a review of all available studies on the development of abuse, addiction, and aberrant drug-related behaviors in patients with persistent pain of noncancer origin who received opioids for pain, only four studies preselected patients for no previous or current history of abuse or addiction (Fishbain, Cole, Lewis, et al., 2008). In these studies, the percentage of patients who became addicted was calculated at 0.19%. A more recent registry study of patients who participated in controlled trials and therefore represented a population from which patients with a history of drug abuse were excluded demonstrated an incidence of 2.6% of drug misuse and no addiction during 3 years of follow-up (Portenoy, Farrar, Backonja, et al., 2007). These data suggest that patients who do not develop a pattern of misuse of psychoactive drugs are at very low risk of developing prescription drug abuse later. None of these data provide insight into the true risk of opioid addiction or abuse among the large population that has a history, or a family history, of alcohol or drug abuse and later receives an opioid for persistent pain.

Ability to Drive and Engage in Other Activities

The effect of opioids on performance of normal activities is sometimes given as reason for withholding opioids. Sometimes employers will not allow patients on opioids to continue their employment. Some prescribers have asked patients to sign agreements that stipulate “no driving” if opioids are taken on a long-term basis (Fishman, Bandman, Edwards, et al., 1999). These outcomes reduce the likelihood that a patient will agree to a trial of this treatment.

According to the opioid treatment guidelines developed by a panel for the APS and the AAPM, the evidence does not support universal prohibition of driving for patients on long-term opioid therapy (Chou, Fanciullo, Fine, et al., 2009). The ability to drive should be assessed in each patient and not prevented in all patients. This is discussed earlier in Chapter 19. Highlights of this discussion are repeated here, and the reader is referred to the earlier discussion for details.

In one study with findings similar to other research, driving tests based on German national recommendations were conducted on 90 healthy controls and 21 patients with noncancer pain who had been treated with transdermal fentanyl for at least 4 weeks without a dose change in the last 12 days (Sabatowski, Schwalen, Rettig, et al., 2003). The median dose of transdermal fentanyl was 50 mcg/h, with a range of 25 to 400 mcg/h. Based on test results, the authors concluded that patients with noncancer pain on stable doses of transdermal fentanyl do not have any clinically significant impairment of psychomotor or cognitive function that would prevent them from driving a car. These results suggest that patients on long-term opioid therapy are probably also able to continue with many other activities. In fact, other drugs such as diphenhydramine (Benadryl) may impair persons more than opioids (Weiler, Bloomfield, Woodworth, et al., 2000).

Whether or not a patient taking opioid analgesics can drive or perform other activities must be decided on an individual basis. Some patients will be able to drive safely, but others may be impaired by opioids. Impairment usually is transient and occurs only at the beginning of opioid therapy or following significant increases in dose, but the reality that some patients have persistent problems requires a careful assessment on a case-by-case basis. Patients who report mental clouding or sedation, or who have signs of impairment on exam should be considered for a change in opioid. It seems prudent to warn all patients that driving ability may be compromised and not to drive if they feel drowsy, dizzy, or impaired in any way, and to advise them of the current literature on driving while taking opioids. In addition, some clinicians advocate asking patients on long-term opioid therapy to obey certain rules if they decide to drive. These rules and a consent form are discussed earlier in Chapter 19 and Box 19-3 on p. 508.

Opioid-Induced Hyperalgesia (OIH)

Hyperalgesia means increased sensitivity to pain. In opioid-induced hyperalgesia (OIH) increasing doses of opioid result in increasing sensitivity to pain (Compton, 2008). OIH has only recently been identified as a clinical reality (Mitra, 2008), but the extent to which it compromises treatment is unknown (Angst, Clark, 2006; Chu, Angst, Clark, 2008). OIH is discussed in more detail in Chapter 11, and the highlights of this discussion are repeated here.

OIH is suspected when increasing doses (usually high, rapidly escalating doses) of opioid fail to relieve pain and actually make pain worse at the original site of pain or at other sites (Chu, Angst, Clark, 2008; Mitra, 2008). OIH may involve unexplained pain, diffuse pain (even the whole body), and diffuse allodynia (Compton, 2008; Chu, Angst, Clark, 2008; Mitra, 2008). To assess the possible presence of OIH, other reasons for failure of the opioid to relieve pain must be ruled out. These include increase in pain pathology, opioid tolerance, opioid withdrawal, pseudoaddiction, and opioid addiction (Compton, 2008). Only when these are ruled out can a diagnosis of OIH be entertained. Table 11-3 (p. 296) gives a brief description of these conditions compared with OIH and suggests some distinguishing characteristics.

Treatment strategies may include opioid dose reduction, opioid rotation, use of N-methyl-d-aspartate (NMDA) receptor antagonists, and continued use of a COX-2 selective NSAID in persistent pain. Once OIH is established, the current opioid dose should be reduced, but the patient is also usually treated with other pain relief strategies as well.

Research has begun to identify potential approaches to preventing OIH. These include proper timing of COX-2 selective NSAIDs in postoperative patients, NMDA antagonists, opioid dose-sparing medications such as certain adjuvants, and avoidance of rapid opioid dose escalation when possible. Theoretically, continued use of COX-2 selective NSAIDs in persistent pain is not only opioid dose-sparing but also may help prevent OIH because these medications reduce the spinal release of excitatory neurotransmitters (Mitra, 2008).

Knowing that long-term opioid therapy, especially if doses escalate rapidly, might actually worsen pain for selected patients adds to the list of reasons to be cautious about this use of opioids. At present, the importance of this outcome is unknown, however, and its reality calls only for careful assessment of patients who do not appear to be improving when an opioid is prescribed.

Other Concerns

Many other concerns about using long-term opioid therapy for patients with persistent noncancer pain exist but are beyond the scope of this book. However, two others deserve at least brief mention: opioid effects on the immune system and opioid effects on the endocrine system in the form of opioid-induced hypogonadism.

A review of the literature by Page (2005) points out that the effect of opioids on immune function has been studied in animals and in humans in the absence of pain and found to suppress immune function. But, in the presence of acute pain, opioid administration in analgesic doses seems to be protective. However, much less is known about the effect on the immune system of prolonged opioid administration in the presence of persistent pain. To date, one small study of 10 patients with persistent pain receiving oral modified-release morphine for 12 weeks indicates that morphine does not influence immune function (Palm, Lehzen, Mignat, et al., 1998). The conclusion was that, at this point in our evidence, concern about opioid effect on immune function is not a reason to withhold opioids from patients with persistent pain. Page (2005) reasons that since it is well known that pain itself suppresses immune function, opioids in analgesic doses could provide relief of pain and thereby provide some relief of the immune suppression of pain.

Negative effects of opioids on the endocrine system have been known for years, but little is written about this. Most of the literature concerns opioid-induced hypogonadism, which is probably common in both male and female patients on long-term opioid therapy (Katz, Mazer, 2009). No standards for laboratory monitoring exist, but recommendations include testing for total and free testosterone (especially in men) and monitoring bone density. Symptoms include decreased libido, erectile dysfunction in men, depression, anxiety, and fatigue. Of course, these symptoms may be due to many other causes such as pain itself. Treatment considerations include opioid rotation and testosterone supplementation. Based on available information, it is not reasonable to withhold opioid therapy because of concerns about endocrine effects of long-term opioid use. These can be monitored and treated.

Treatment Guidelines

The first treatment guidelines developed by professional organizations and designed specifically for the use of long-term opioid therapy for persistent noncancer pain were published in 2009 by a panel convened by the APS and the AAPM (Chou, Fanciullo, Fine, et al., 2009). By contrast, treatment guidelines for cancer pain were published by the World Health Organization (WHO) in the 1980s (WHO, 1986), quickly followed by the APS (APS, 1987) guidelines for acute pain and cancer pain but not for persistent noncancer pain. The Agency for Health Care Policy and Research (AHCPR) then developed guidelines for acute pain (Acute Pain Management Guideline Panel, 1992) and cancer pain (Jacox, Carr, Payne, et al., 1994) but again, not for persistent noncancer pain. Notably, it was approximately 2 decades between the development of guidelines for acute and cancer pain and guidelines for the pharmacologic treatment of persistent noncancer pain. During those years and up to the present time, considerable controversy exists about the long-term use of opioids for persistent noncancer pain.

Despite this controversy, the use of opioids for persistent noncancer pain has increased considerably. Although evidence is limited, the APS-AAPM panel concluded that long-term opioid therapy can be effective with carefully selected patients with persistent noncancer pain. The guideline includes, among other things, a discussion of informed consent and opioid management plans, initiation and titration of long-term opioid therapy, and monitoring of patients.

This guideline is a step in the right direction but has been subject to some criticism, making it important to remember that guidelines are not rules—they are simply guides. Some recommendations are considered questionable since they were presented as “strong recommendation, low-quality evidence” (Leavitt, 2009).

Another criticism is related to a previously registered serious objection to the Washington State Agency Medical Directors’ Group (2007) recommendation in their guidelines that doses greater than 120 mg/day of oral morphine or equivalents should rarely be given and only prescribed after consultation with a pain management expert (Fishman, Webster, 2009). Yet, based on low-level evidence, the APS-AAPM defined a “high” dose of opioid as greater than 200 mg/day of oral morphine or its equivalent and stated that such doses require more intense monitoring.

Another guideline from the American Geriatrics Society (AGS) addresses the pharmacologic treatment of persistent noncancer pain in people 75 years or older (AGS, 2009). Previously, NSAIDs were recommended if acetaminophen did not relieve pain. However, new evidence has drawn attention to the dangerous adverse effects of NSAIDs, such as cardiovascular risk, nephrotoxicity, and gastrointestinal (GI) toxicity (see Section III). Since NSAIDs may result in life-threatening problems, opioids are suggested as a safer alternative in many older adults (AGS, 2009).

Regulatory Issues

The APS-AAPM panel points out that surveys show that prescribers have limited understanding of the laws, policies, and other matters that govern the prescribing of opioids, and that this may have an impact on the care patients receive (Chou, Fanciullo, Fine, et al., 2009). Our impression is that fear of regulatory scrutiny causes prescribers to be fearful of long-term prescribing of opioids and in turn causes them to be overly cautious of prescribing opioids. For their own protection and the patient’s benefit, prescribers should find out about the numerous policy changes that have occurred in recent years. The Pain and Policy Studies Group, University of Wisconsin Database, provides information on state laws, regulations, and other official government policies, and is available at www.painpolicy.wisc.edu/matrix.htm.

Opioid Safety Regulations: Risk Evaluation and Mitigation Strategy (REMS)

A defining consideration in the approval of any drug by the United States Food and Drug Administration (U.S. FDA) is that the benefit of the drug must outweigh its risks. In the case of opioids, abuse potential and the consequent concerns for public health are receiving increasing attention in the review process for new drugs, while new regulations are being considered for some drugs already marketed.

In February of 2008, a new federal law gave the U.S. FDA expanded powers to regulate both new and established medications. One of the provisions authorizes the U.S. FDA to require that a drug manufacturer submit a Risk Evaluation and Mitigation Strategy (REMS). REMS typically include patient and prescriber education. Some may require restricted distribution through specified pharmacies and registries of approved patients, prescribers, and pharmacists. The most restrictive REMS requires that a courier deliver the prescription to the approved pharmacy and also deliver the medication to the patient (Biodelivery Sciences International, 2009) (See U.S. FDA, 2010 for approved REMS).

Manufacturers of methadone and all modified-release opioids were informed in early 2009 that they would be required to develop a REMS for each of their products. A “Draft Guidance” document for opioid REMS has been published (U.S. FDA, 2009d) but a final rule is unlikely before 2011. In the meantime, individual product REMS will be required for any newly approved opioid analgesic.

The REMS approach for opioid analgesics is controversial. Patient advocacy groups and professional societies have endorsed the goals of safe use and avoidance of abuse and diversion. However, they have expressed concerns about the potential unintended consequence of decreased access to appropriately prescribed opioids (American Pain Foundation, 2009;American Pharmacists Association, 2009; Inturrisi, 2009; Shane, 2010). There is broad consensus that patient and public safety must be considered at all levels of opioid development, approval, and clinical use. It will be some time before either positive or negative outcomes of opioid REMS are known.

Patients with Pain and Active Addictive Disease

Patients who are actively using alcohol and other drugs may come to the inpatient or outpatient health care setting under the influence of these drugs. Treatment of pain may be difficult if the patient is unable to give consistent answers to questions about the pain or the drugs he or she has taken, sometimes causing a delay in treating pain. However, pain treatment should begin as soon as possible. If the patient is too sedated to safely receive opioids, the use of NSAIDs, regional anesthetic techniques, adjuvant analgesics, or nonpharmacologic methods of pain control is recommended.

If the patient has been using opioids, naloxone or other opioid antagonists should not be administered for the purpose of decreasing the opioid’s effect unless the patient’s life is in danger. Opioid antagonists could increase the patient’s pain and throw the patient into withdrawal.

As soon as possible, obtain information from the patient and family about which drugs the patient has been abusing and all medications that have been prescribed. Become familiar with signs of withdrawal from each of the drugs and how to minimize withdrawal symptoms, such as by an appropriate tapering of the drug or an appropriate substitute. Obtain protocols for assessing and treating withdrawal from opioids, other drugs, and alcohol (e.g., to assess symptoms of alcohol withdrawal, obtain a protocol from http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.table.4060; for clinical detoxification protocols, also see http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.table.4060. Withdrawal from alcohol can be life-threatening if not assessed and treated properly.

Box 20-1 presents general guidelines for treating patients with addictive disease and pain in all clinical settings, and more specific guidelines for treating patients in the inpatient setting and in the outpatient setting.

Patients in Recovery from Addictive Disease

Most clinicians, persons with addictive disease, and their families expect complete abstinence from the drug of abuse and other drugs with abuse potential. However, it is not realistic to expect all patients recovering from addictive disease to be totally abstinent (Passik, Kirsh, 2004). Harm reduction may be a more realistic goal and should not be considered a failure. Some patients may find it possible to cut down on their drugs of abuse or find a less harmful way to consume the drug, such as smoking heroin instead of sharing needles to give it IV. Others may need medically prescribed medications, such as opioids or benzodiazepines.

Alcoholics Anonymous (AA) published a pamphlet in 1984 to address the use of medications and other drugs while in recovery from alcoholism. They point out that while some members of AA believe that no one in AA should take any medication, this can be disastrous for some people. Those with depression, schizophrenia, manic depression, epilepsy, and others requiring medication may meet with serious consequences, such as suicide or seizures, if they do not take their prescribed medications, some of which admittedly carry the potential for abuse. This pamphlet may be ordered by writing AA World Services, Inc., Box 459, New York, NY 10163 or by contacting AA at 212-870-3400. Having this available is often reassuring and informative for staff as well as patients with addictive disease and their families. Nonetheless, whether or not to take opioids for pain relief is the patient’s decision, not the clinician’s.

Patients who are in recovery and are totally abstinent are often fearful of relapse, and clinicians should discuss any intent or recommendation to use opioids or other psychoactive medications in their treatment. Establish from the beginning that the patient can make the final decision about the use of opioids or other drugs. In the past, clinicians used to make this decision for the patient and simply withhold opioids. Assure the patient that this will not happen. Discuss alternative options, such as nonopioids (NSAIDs and acetaminophen), regional anesthetic techniques, adjuvant analgesics, and nonpharmacologic methods, with those who do not want to take an opioid for pain relief.

Address fear of relapse by encouraging patients to continue and increase their activities with their recovery program. Remember to include the patient’s family in these discussions because they may be equally or even more fearful of relapse.

Some patients recovering from addiction to opioids may be receiving opioid agonist therapy with either methadone or buprenorphine. These patients are likely to be undertreated for acute pain due to several misconceptions (Alford, Compton, Samet, 2006). Some clinicians erroneously believe that the maintenance opioid dose will suffice to relieve pain, and, therefore, fail to take additional action to provide pain relief. Other misconceptions are that adding another opioid analgesic may result in addiction relapse or cause respiratory depression. If these misconceptions are not corrected, the patient with acute pain will likely suffer, and the patient’s reports of pain may be seen as manipulation to obtain more opioids.

If the patient is receiving methadone maintenance therapy (MMT) a common approach is to continue the methadone maintenance dose and add short-acting opioids, titrating the dose upward until pain relief is achieved (Alford, Compton, Samet, 2006). MMT has been used for decades, but buprenorphine maintenance therapy was only approved in the United States in 2004. Research and clinical experience have not yet identified the most effective approach for relieving pain in buprenorphine-maintained patients. Four options were suggested by Alford, Compton, and Samet (2006). The simplest one consisted of continuing the buprenorphine maintenance therapy and titrating a short-acting opioid analgesic to a dose that relieves the pain. A similar approach was suggested by other researchers in which the maintenance dose is given in divided doses and an additional opioid agonist such as morphine is added and titrated to effect (Vadivelu, Hines, 2007). In a study of managing acute postpartum pain in one group of patients on MMT (N = 10) and the other maintained on buprenorphine (N = 8), ibuprofen was used along with adding an opioid agonist for both groups and appeared to be beneficial in relieving pain (Jones, O’Grady, Johnson, et al., 2009). Patients on either form of maintenance therapy are likely to require higher doses of opioid for pain relief than the usual opioid-naïve patient. Box 20-2 presents guidelines for the management of pain in the patient recovering from addictive disease.

Comments on the Treatment of Pain in Patients with Addictive Disease

This aspect of patient care, relieving pain when the patient has addictive disease, especially the active addict, is one of the most challenging situations clinicians encounter. Knowledge of pain, addictive disease, and regulations governing the prescribing of controlled substances are required. It takes courage—the clinician’s fear of endangering his or her license is not unfounded. Extensive experience and considerable self-awareness are always helpful. And the clinician needs to be willing to spend the extra time these patients usually require. Too often patients recovering from addictive disease are dismissed from practice when any suggestion of relapse or abuse occurs, and this is understandable in view of the above demands on the clinician. Hopefully, such patients are referred to others who are more prepared or willing to care for these patients. Unfortunately, an appropriate referral cannot always be made. So, who is going to be responsible for the care of these patients? This question has yet to be answered. Following is one response.

A pain specialist speaking about addictive disease to an audience of other pain specialists received this comment from a member of the audience, “These patients are too difficult, take up too much time, and put me in legal jeopardy. I simply have to discharge them from my practice.” To this the speaker replied, “If we, the pain specialists, don’t treat them, who will?”

Neonatal Abstinence Syndrome

Physical dependence can occur in an infant whose mother took opioids during pregnancy, and abrupt discontinuation of the opioid can result in withdrawal symptoms after birth. These symptoms are collectively called neonatal abstinence syndrome and are characterized by neuralgic excitability (e.g., tremor, irritability, hypertonicity, abnormal crying, insomnia, and rarely seizures); GI dysfunction (e.g., nausea, vomiting, diarrhea); and autonomic dysfunction (e.g., fever, chills, nasal congestion). It is important to understand that physical dependence is not addiction. Addiction implies the psychological dependence on a particular drug and a cause-and-effect mode of thinking. Infants are incapable of this higher-level cognitive recognition and therefore cannot become addicted (Stevens, 1999). (See Chapter 11 for the difference between addiction and physical dependence.)

Not all infants born of mothers who take opioids during pregnancy will exhibit neonatal abstinence syndrome, as noted in the case study described earlier (Einarson, Bozzo, Taguchi, 2009). Studies have consistently shown that approximately 40% of infants will not develop symptoms (Berghella, Lim, Hill, et al., 2003; Ebner, Rohrmeister, Winklbaur, et al., 2007). Research is conflicting regarding whether or not the dose of opioid the mother takes influences the severity of symptoms. Whereas one retrospective review showed that the higher the methadone dose the more likely it was that the infant would have withdrawal symptoms and the longer the duration of treatment (Lim, Prasad, Samuels, et al., 2009), another retrospective review showed no correlation between methadone dose and severity or duration of neonatal abstinence syndrome (Berghella, Lim, Hill, et al., 2003).

Expecting a newborn to endure neonatal abstinence syndrome without appropriate treatment is unethical, dangerous, and not recommended. Rather, symptoms are prevented with the administration and gradual tapering of a mu opioid over several days; oral morphine or tincture of opium is usually used for this purpose (Stevens, 1999). A Cochrane Collaboration Review found that opioids and supportive care compared with supportive care only for the treatment of neonatal abstinence syndrome reduced the time to regain birth weight and the duration of supportive care (Osborn, Jeffery, Cole, 2005a). Length of hospitalization was longer in those who were treated with morphine, but it was not clear if this was related to infant status. The review also revealed that oral morphine was associated with better outcomes than diazepam and prevented seizures better than phenobarbital. Another Cochrane Collaboration Review found that phenobarbital was more effective than diazepam for neonatal abstinence syndrome (Osborn, Jeffery, Cole, 2005b). Phenobarbital was associated with shorter hospital stays than oral morphine, but the researchers observed that this may have been related to the willingness of health care providers to discharge an infant with a prescription for phenobarbital but not with one for morphine (Osborn, Jeffery, Cole, 2005b). A study of the babies of women who attended an addiction treatment clinic found that oral morphine (0.05 to 0.1 mg/kg/dose PRN) was more effective than phenobarbital (5 to 10 mg/kg/day) for the treatment of neonatal abstinence syndrome, and unlike the previously mentioned study, found that morphine was associated with a significantly shorter treatment time (Ebner, Rohrmeister, Winklbaur, et al., 2007).

In summary, the current research suggests that oral morphine is the preferred drug for the prevention and treatment of neonatal abstinence syndrome. During administration, infants should be monitored closely, and other comfort measures, such as swaddling, massage, relaxation bathing, waterbeds, and pacifiers, should be provided (Osborn, Jeffery, Cole, 2005a).

Selection of Opioid Doses in Patients Unable to Report Pain

Nurses often ask how to select a starting opioid dose and how to know if that dose is effective in patients who cannot report their pain. Chapter 16 discusses in detail the method used to determine opioid doses, and this method is applicable to patients who cannot report pain. In most cases, pain is assumed to be severe in critically ill patients based on the presence of significant pathology (Puntillo, Pasero, Li, et al., 2009), and doses are selected accordingly (e.g., 2.5 mg/h IV morphine or equivalent starting dose in an opioid-naïve adult; higher doses will be required for opioid tolerant patients). As in patients who can report pain, pain is also prevented prior to painful procedures with IV opioid bolus doses (e.g., 1 to 2 mg). If present, changes in behaviors after an opioid dose is administered or an opioid infusion is initiated are used to evaluate analgesic effectiveness. In patients who are unresponsive, no change in behavior will be evident to guide assessment of analgesic effectiveness; therefore, the optimized opioid dose is continued (Pasero, 2009a).

Weaning from the Mechanical Ventilator

When critically ill patients show improvement, they are weaned from mechanical ventilation. Often opioids are discontinued before beginning the weaning process out of a fear that opioids will produce adverse respiratory effects and impede weaning. However, the fear of respiratory depression, cited as the main reason for stopping opioids before weaning, usually is unfounded in critically ill patients. Most critically ill patients will receive opioids long enough for some tolerance to develop, and tolerance to respiratory depression develops relatively rapidly within days of regular dosing. Therefore, fear of respiratory depression should not be a barrier to continuing opioids for patients who have been receiving them for several days or longer (APS, 2003).

In addition, loss of pain control can cause ventilator weaning to fail. Unrelieved pain can contribute to pulmonary dysfunction (Ghori, Zhang, Sinatra, 2009; Jacobi, Fraser, Coursin, et al., 2002). Even when the source of pain is remote from the thoracic and abdominal region, respiratory dysfunction can occur. Involuntary responses to pain cause reflex muscle spasm at the site of tissue damage and in muscle groups above and below the site. Patients with pain also voluntarily limit their thoracic and abdominal muscle movement in an effort to reduce the pain they are experiencing.

The measurable respiratory effects of severe pain are small tidal volumes and high inspiratory and expiratory pressures, as well as decreases in vital capacity, functional residual capacity, and alveolar ventilation (Ghori, Zhang, Sinatra, 2009). If adequate pain relief is not provided, these effects can progress to significant pulmonary complications, such as atelectasis and pneumonia.

Abrupt discontinuation of opioids can have other undesirable consequences besides loss of pain control. At the time of weaning, many critically ill patients have been receiving opioids long enough to have developed physical dependence. If the opioid is stopped abruptly for weaning, physically dependent patients will experience withdrawal syndrome. Signs of withdrawal include restlessness and agitation and may be confused with failed weaning or “ICU psychosis.” The practice of abrupt discontinuation of opioids can result in inaccurate assessment of the patient’s response and inappropriate treatment (e.g., benzodiazepines to sedate the patient).

If a reduced opioid dose is required for successful weaning, using a multimodal analgesic approach may make it easier to do so without compromising good pain control. If an NSAID is not contraindicated and is not being administered around the clock (ATC) already, one can be added before weaning to allow a reduced opioid dose. Acetaminophen can be given rectally for additional analgesia. Anticonvulsants, such as gabapentin, can be added to treat neuropathic pain and prevent the development of persistent pain. Other appropriate nonsedating adjuvants, such as local anesthetics via continuous peripheral nerve block or added to epidural opioids, should be considered.

The lack of a respiratory depressant effect with dexmedetomidine (Precedex) has implications for its use during weaning from mechanical ventilation and extubation. A study of patients who had failed previous attempts at ventilator weaning secondary to agitation unresponsive to traditional sedatives described successful extubation of 14 of the 20 patients who were given dexmedetomidine (Arpino, Klafatas, Thompson, 2008). Other positive results were a reduction in concomitant sedative and analgesic use and minimal adverse effects. Dexmedetomidine has also been reported to facilitate terminal weaning and withdrawal of ventilatory support at end of life in palliative care (Kent, Kaufman, Lowy, 2005) (see Section V for more on dexmedetomidine).

The intraspinal routes are frequently used to deliver opioids to the critically ill. One of the benefits of intraspinal analgesia in mechanically ventilated patients is excellent analgesia with lower opioid doses and less threat of respiratory depression during weaning. In addition, a number of studies have demonstrated improved pulmonary function with intraspinal analgesia (see Chapter 15 for research and detailed discussion of intraspinal analgesia). Continuous peripheral nerve blocks, which rely on local anesthetics for analgesia, may be ideal for some patients in the ICU (see Section V).

“In the context of the caring relationship, nurses perform a primary role in the assessment and management of pain and other distressing symptoms in dying patients. Therefore, nurses must use effective doses of medications prescribed for symptom control and nurses have a moral obligation to advocate on behalf of the patient when prescribed medication is insufficiently managing pain and other distressing symptoms. The increasing titration of medication to achieve adequate symptom control is ethically justified.” (p. 1, American Nurses Association, 2003)

Treatment of Dyspnea

Dyspnea is a very distressing symptom that can occur in both opioid-naïve and opioid-tolerant patients (Bruera, Currow, 2009). It is a common symptom in many cancer and noncancer-related chronic illnesses (Newton, Davidson, Macdonald, et al., 2008). It is often present at end of life and is an independent predictor for shorter survival among cancer patients (Bruera, Currow, 2009). An early prospective study of hospice patients in the last 6 weeks of life found that as many as 70% suffered from the condition (Reuben, Mor, 1986). There is no consensus on how to measure breathlessness (Bruera, Currow, 2009). Patients’ subjective descriptions of dyspnea vary widely, for example, “difficult, labored, uncomfortable breathing” and “the sensation of breathlessness or air hunger” (American Thoracic Society, 1999). The condition is associated with significant patient distress and poor quality of life (Edmonds, Higginson, Altmann, et al., 2000). It often coexists with fatigue, depression, and anxiety (Bruera, Currow, 2009).

Clinical assessment of dyspnea is described as having four components: (1) obtaining a comprehensive history about onset and exacerbating and relieving factors; (2) performing a physical examination for causes; (3) assessing the intensity of unpleasantness of breathlessness with a scale (e.g., 0-to-10) to establish a baseline; and (4) tracking dyspnea along with other symptoms to evaluate its impact on quality of life (Bruera, Currow, 2009). A variety of medications and routes of administration have been used to treat dyspnea, although opioids have been the mainstay for treatment of dyspnea for many years (Pasero, Portenoy, McCaffery, 1999). A Cochrane Collaboration Review concluded that there was evidence to support the use of systemic (oral, parenteral) but not nebulized opioids to treat dyspnea (Jennings, Davies, Higgins, et al., 2001). The researchers encouraged more research with larger numbers of patients, the use of standardized protocols, and evaluation of quality of life measures. A later review of 20 articles with evaluable evidence reached similar conclusions (Joyce, McSweeney, Carrieri-Kohlman, et al., 2004). In their evidence-based guidelines on interventions to improve the palliative care of pain, dyspnea, and depression, the American College of Physicians recommended the use of opioids for both pain and dyspnea based on a history of proven effectiveness (Qaseem, Snow, Shekelle, et al., 2008).

Oxygen has been used for treatment of dyspnea, but a prospective study (N = 46) found no correlation between intensity of dyspnea and oxygen saturation in either hypoxic or nonhypoxic palliative care patients who received -oxygen (4 L/min) by nasal cannulation; opioids on the other hand, significantly reduced the intensity of the patients’ dyspnea (Clemens, Quednau, Klaschik, 2009). A small randomized controlled, double-blind, crossover trial (N = 9) administered placebo or 5 mg of subcutaneous morphine to 7 opioid-naïve older adults and 3.5 mg of subcutaneous morphine in addition to their usual oral morphine doses to 2 older adults (all patients had cancer) and found that the subcutaneous morphine significantly improved the symptoms of dyspnea and did so without compromising respiratory effort or oxygen saturation (Mazzocato, Buclin, Rapin, 1999). Another small study (N = 6) found similar results in patients with terminal amyotrophic lateral sclerosis (Clemens, Klaschik, 2008a).

Clinicians are sometimes reluctant to use opioids to treat dyspnea, citing concern that adding another or more opioid to the opioid a patient is already receiving for analgesia, or starting an opioid in an opioid-naïve patient, increases the risk of opioid-induced sedation or respiratory depression. Studies have not confirmed this fear.

A randomized, double blind, placebo-controlled cross-over trial found that oral modified-release morphine (20 mg) provided significant improvement in refractory dyspnea in 48 opioid-naïve patients (Abernethy, Currow, Frith, et al., 2003). Treatment was tolerated well with minimal adverse effects, and patients cited improved sleep as a major benefit of treatment. Hydromorphone has also been used for dyspnea. A small prospective study demonstrated that titrated doses of oral hydromorphone produced considerable and sustained improvement of moderate or severe dyspnea during both rest and mild activity in 14 palliative care patients (Clemens, Klaschik, 2008b). The mean single dose of hydromorphone was 2.5 mg (0.5 to 6.0 mg range). Half of the patients were opioid-naïve. An important finding was that there were no significant increases in carbon dioxide (CO₂) or decreases in oxygen (O₂) saturation. Treatment with hydromorphone was continued in all patients after the study was completed.

As mentioned earlier in the chapter, more well-controlled research is needed on the use of nebulized opioids (see Chapter 14). Nevertheless, morphine by this route has been used for many years to treat dyspnea. A prospective, nonrandomized study (N = 46) used transcutaneous CO₂ measurement and pulse oximetry (O₂ saturation) and found that there was no higher risk of respiratory depression in opioid-naïve compared with opioid-tolerant palliative patients treated with nebulized morphine (Clemens, Quednau, Klaschik, 2008). The patients experienced a significant decrease in the intensity of dyspnea and respiratory rate. These studies and clinical experience support the recommendation that carefully titrated doses of opioids for treatment of dyspnea should be administered to patients who are suffering from the distress of having to fight to breathe.