Constipation

This is a common problem with incidence between 40% and 90% of patients treated with opioids and may appear after a single dose. The consequence of constipation along time is related to increased morbidity and mortality and worsening of patients' quality of life. Chronic constipation results in effort to evacuate, formation of hemorrhoids, rectal region pain and burning sensation, intestinal obstruction with risk of rupture and death⁴. Decreased intestinal mobility results from the activation of mu receptors in the gastrointestinal tract, acting directly on the enteric nervous system or decreasing parasympathetic autonomic flow⁵. However, tolerance seen for nausea, sedation and respiratory depression does not occur for opioid-induced constipation. So, there is no improvement of symptoms during the use of opioids and constipation should be adequately monitored and managed. Roma III criteria may be used to define intestinal constipation and are based on: effort to evacuate, hardened or fragmented stools, sensation of incomplete evacuation, sensation of anorectal obstruction or blockade, manual maneuvers to help evacuation and less than three evacuations per week (Table 1).

The presence of two or more of such criteria in the last six months characterizes intestinal constipation, being that each criterion may be considered positive when reaching the following cutoff points: 1) evacuation effort in at least 25% of defecations - answer equivalent to "frequently" (question A≥2); 2) hardened or fragmented stools in at least 25% of defecations - answer equivalent to "frequently" (question B≥2); 3) sensation of incomplete evacuation in at least 25% of defecations - answer equivalent to "sometimes" (question D≥1); 5) manual maneuvers to help at least 25% of defecations - answer equivalent to "sometimes" (question E≥1); and 6) less than three evacuations per week⁶.

With regard to constipation, it is necessary to reeducate life habits (alcoholism, smoking and practice of physical activities) and dietary habits (fluid and fiber ingestion) which influence intestinal mobility pattern. The recommendation is to consume 14g of fibers for each 1000kcal ingested and adequate ingestion values for fluids for sedentary people is 3.7L/day for males and 2.7L/day for females, being these values higher for physically active people⁷. After optimizing such factors, laxatives may be associated in doses recommended by the literature, respecting contraindications (Table 2).

Effective constipation management requires de use of opioid antagonists, with peripheral action on mu receptors, such as methylnaltrexone and alvimopan. These agents act on the gastrointestinal tract sparing central opioid analgesic effect⁸. Recommendations of this article are described in tables 3 and 4^8-15.

Urinary retention

Opioids may decrease tone and contraction strength of the detrusor muscle of the bladder, the sensation of plenitude and the desire to urinate, in addition to decreasing voiding reflex. This effect is more common during acute pain with prevalence from 4% to 18%. Important: 1) investigate other causes for urinary flow decrease, such as renal failure, ureteral obstruction or hypovolemia; 2) avoid anticholinergic drugs; 3) decrease opioid dose; 4) perform bladder voiding maneuvers or bladder catheterization if necessary. Urinary retention may be caused by central or peripheral action on mu receptors and may be partially reverted by antagonists¹⁶.

Cardiovascular effect

Cardiovascular effects are not very common. Morphine releases histamine, causing vasodilation and hypotension, which are partially reversed by antagonist H1 or totally reversed by naloxone. Parasympathetic stimulation may also contribute to bradycardia¹⁷. Prolonged QT interval and torsade des pointes(Tdp) syndromes have been recently described, with ventricular tachycardia and cardiac arrest in patients under chronic methadone¹⁸. Mortality may reach 17% and previous electrocardiographic monitoring is recommended before the use of such agents. In heroin-addicts being treated with methadone, the occurrence of tachycardia related to prolonged QT interval (above 500ms) was 16% and of Tdp rhythm of 3.6%¹⁹.

Some authors have observed that interval above 30ms should be considered significant and above 60ms a risk factor for Tdp rhythm. This, however, is more common in individuals using methadone doses above 40mg or in concomitant use of CPY3A4 enzyme inhibitors, such as fluoxetine, sodium valproate, clarithromycin and fulconazole. Other drugs, such as tricyclic antidepressants, neuroleptics and erythromycin have been also described as agents which may prolong QT interval. So, it is important to monitor patients using CPY3A4 enzyme inhibitors, those with low potassium levels or altered liver function²⁰. So, we conclude that:

1) The possibility of elongating the QT space (including the polymorphic type) and the evolution to ventricular arrhythmia should be considered when using opioids, especially methadone;

2) The use of concomitant drugs which prolong QT interval or which share common metabolism pathways with methadone should be avoided.

Effects on the immune system

Opioids have been implied in the increased incidence of infection in heroin-addict patients and as a facilitator for the pathogenesis of the acquired immunodeficiency virus. Chronic opioid administration may inhibit cell immune response, the production of antibodies, natural killer (NK) cell activity and the expression of pro-inflammatory cytokines²¹. These effects may be related to the action on MOR receptors and to the inhibition of macrophages phagocytic activity and to the action on KOR receptors. The action on KOR receptors, however, increases NK cells activity and humoral immune response²².

Although several studies point to opioids immunosuppressive effect, the clinical relevance of such observations is still uncertain and works just as a pre-requisite for new investigations in this area. Final recommendations for the use of opioids, in the most different clinical practice situations, with regard to immune consequences of such drugs still cannot be made. Since each substance seems to have a different effect, additional studies with different opioids, in addition to morphine, should be carried out. Still, specific subpopulations, such as immunosuppressed and patients in critical stage, should also be object of research.

Opioid-induced tolerance and hyperalgesia

Most of the times, increasing opioid dose is related to disease progression or tolerance. Tolerance implies the need for increasingly higher doses to obtain the same effect. That is, there is decrease in effectiveness along time. There are two types of tolerance: the innate, which depends on genetic inheritance and the acquired (pharmacokinetic, pharmacodynamic and learned). Pharmacokinetic tolerance is related to changes in drug metabolism after repeated administrations, leading, then, to enzyme induction. However, pharmacodynamic tolerance may be associated to increased opioid receptors. On the other hand, the learned tolerance is related to concepts. Patients take more drugs because they believe they are not effective or that taking more they will feel better. Opioid tolerance is not crossed, and this concept is the basis for the rotation of such agents²³. Attention is to be paid to opioid-induced toxicity, clinical presentation characterized by sensitivity changes (allodynia and hyperalgesia), by the need for increasingly higher opioid doses, myoclonus, seizure and cardiac arrest²⁴.

In opioid-induced hyperalgesia, there is a down-deviation of the dose/effect curve, that is, the analgesic effect decreases along time with a certain opioid dose and there is no improvement with dose increase - on the contrary, there may be worsening of pain. Pain is more severe than the original or initial pain, it is poorly defined in terms of quality and location, with decreased tolerability threshold²⁵. Recommendations to decrease hyperalgesia are: 1) dose adjustment or opioids rotation; 2) switch to methadone when there is suspicion of hyperalgesia caused by a different opioid; 3) switching to methadone does not eliminate the possibility of hyperalgesia²⁶. There are no well-controlled studies assuring the use of dextromethorphan, memantine, propofol, naloxone and ketamine to treat opioid-induced hyperalgesia.

Hormonal alterations

Opioids may induce endocrinopathy. There is report of reduction of total and free testosterone, estrogen, LH, GnRH, DHEA, DHEAS, ACTH, CRH and cortisol²⁷. Most studies, however, are focused on androgenic hormones. It has been reported erectile dysfunction, libido reduction, depression, anemia and fatigue. There is free and total testosterone reduction between 1 and 4h after intravenous opioid administration, returning to normal values 24h after drug withdrawal. In chronic pain patients under opioids, smoking predisposes to this alteration. It also seems that this action is different for different opioids, being lower for buprenorphine as compared to methadone. Eighty seven percent of patients using methadone in doses above 100mg per day have major erectile dysfunction and all (100%) have decreased testosterone levels. Transdermal testosterone, however, may decrease several alterations induced by chronic opioid use²⁸. In females, there may be estrogen decrease with depression, dysmenorrhea, sexual dysfunction and mineral bone loss. Bone loss in the elderly population leads to increased risk for osteoporosis and fractures. Hormonal replacement, however, not always revert symptoms, fact which favors the hypothesis that there are other pathophysiological mechanisms involved²⁹.

Sedation and cognitive disorders and myoclonus

Opioid-induced sedation and sleepiness may be related to its anticholinergic activity. Treatment includes diagnosing and treating comorbidities, dose interruption or reduction of other central nervous system depressants, opioid rotation, decrease the dose and use of psychic stimulants. In cancer patients in chronic use of opioids, methylphenidate (in dose between 10 and 20mg/ day) may significantly increase psychomotor activity scores in up to 35% and sleepiness in up to 61% as compared to placebo. In addition, methylphenidate may decrease pain and rescue doses. Other less used agents are dextroamphetamine (2-20 mg/day), caffeine, donepezil and madafinil³⁰. Statements and recommendations about this subject are shown in table 7³¹.

Sleep disorders

Opioids also change the sleep and wake relationship, decrease total sleep time and efficiency, delta waves and REM sleep. It is possible that opioids change the dynamics of neurotransmitter circuits which regulate impulses converging to brainstem and those coming from pontinecholinergic projections. Morphine seems to regulate acetylcholine release in the reticular formation of the pons through the activation of the GABAergic pathway³². A study with cancer patients under morphine or methadone has shown that there has been only decrease of sleep timing stages 3 and 4, and increase in superficial sleep timing in almost 50%³³.

Psychomotor activity

During early treatment with opioids the ability to handle heavy equipment or to drive vehicles may be impaired. This, however, does not occur with patients who have reached stable doses of such agents. So, one cannot prohibit patients of performing their motor function; however care is recommended in early treatment stage³⁴.

Respiratory depression

The incidence of respiratory depression is low (0.002-1.2%) and there are few reports in the literature with the chronic use of opioids. Tolerance to this adverse effect is developed in a few days. On the other hand, the risk is increased for patients with sleep apnea, morbid obesity and chronic obstructive pulmonary disease (COPD). From 140 patients with chronic pain and using opioids, who were submitted to polysomnography, 75% had obstructive sleep apnea with significantly higher rates as compared to general population (2-4%)³⁵. This has also been related to daily methadone dose associated to a benzodiazepine.

In reference studies, for the venous route, with self-controlled analgesia pump, the incidence of bradypnea is approximately 1.6% and of hypoxia of 15.2%. For the epidural route it is between 0.2% and 1.6% and for the subarachnoid route between 0% and 3%³⁶. However, the association with drugs depressing the central nervous system (benzodiazepines, alcohol, inhalational anesthetics, tricyclic antidepressants, anti-histamines, IMAO, clonidine and neuroleptics) should be avoided. Such associations may lead to higher risk of respiratory depression. Also, when using any opioid, dose should be titrated according to patients' need and the type of aggressive stimulation, to avoid using doses above those necessary. It is important to inform patients that minimum effective dose to reach analgesia without adverse effects may be used progressively and that additional doses shall be used to reach the desired effect. So, to treat respiratory depression it is recommended: dose titration and reduction, use of opioid antagonist (intravenous 1-5µg/kg or 5µg/kg/h naloxone). On the other hand, buprenorphine-induced respiratory depression is only reverted by doxapram (IV 0.5-1.5 mg/kg every 5 minutes, maximum dose 2 mg/kg)³⁷. Statements and recommendations for respiratory depression are shown in tables 5 and 6^38-43.

Pruritus

Mechanisms involved with opioid-induced pruritus genesis seem to involve the excitation of µ receptors in neurons not related to nociception and in motor neurons related to withdrawal reactions. It is possible that pain and pruritus are controlled by similar mechanisms or that pruritus represents a specific type of pain because both evoke motor responses (removal and scratching, respectively) which may be conducted by the same type of nervous fibers since no morphological differences were found between pain and pruritus receptors⁴⁴. Pruritus may also be related to histamine release by mast cells. Fentanyl and sufentanil, however, may induce pruritus without histamine release. This effect occurs after administration by any route. Anti-histamines (diphenhydramine), ondansetron, opioid rotation, nalbuphin or naloxone may be used for treatment^45,46.

Nausea and vomiting

Their incidence is approximately 10-40%, however tolerance is rapidly developed (5-10 days). The mechanism is by activation of the chemoreceptor trigger zone, gastric stasis and increased vestibular system sensitivity. However, there are several other reasons for patients presenting such symptoms (other drugs, uremia, liver failure, hypercalcemia, increased intracranial pressure and gastrointestinal obstruction). Treatment includes reverting comorbidities and general measures such as: hydration, fractioned diet, oral hygiene, drug adjustment, use of other administration route different from oral, use of drugs. Recommendations of this article are shown in tables 8 and 9^47-50.

Abuse and addiction

When addressing abuse and addiction it is important to accurately define clinical syndromes (Table 1)⁵¹. A recent study has shown that the prevalence of addiction may vary from 0% to 31% (mean of 4.5%)⁵². On the other hand, the real prevalence of opioid-induced addiction is not known; however, it seems to be higher than expected and may vary from 0% to 50%^53,54. This variation in prevalence may be due to differences in methods and risk factors when evaluating addiction, to treatment duration and to the observation of the study.

More common drugs looked for illicitly are oxycodone and hydrocodone in higher proportion than morphine, fentanyl and hydromorphone (25% of cases). On the other hand, among street users, methadone is the most widely used and sold drug⁵⁵.

Risk factors for opioids addiction and abuse include age (from 18 to 24 years of age), male gender, subjective pain complaint in different body regions, low back pain, previous history of alcohol abuse, Cannabis or illicit drugs, presence of psychiatric disorder (anxiety or depression) or of psychosocial stress, use of psychotropic drugs, increased level of tolerance to pain, eagerness to get the drug, criminal history, smoking, Caucasian race (for receiving more analgesics in emergency units), presence of pain-related functional limitation, history of post-traumatic stress, unemployment and hepatitis C (Table 10)^56,57.

With regard to genetic factors, variations in coding regions 118 A>G and 17 C>T SNP of the µ opioid receptor gene (OPRM1) and 36 G>T SNP of the OPRK1 receptor gene and 80 G>T and 921 C>T for the OPRD1 gene may increase the risk of abuse. Another polymorphism of pre and pro-encephalin (PENK) and of melanocortin type 2 receptor (MC2R) is associated to opioid addiction in several studies⁵⁸. The use of tests to identify the potential for opioid addiction and abuse should be according to risk stratification: 1) low risk, no history of substance abuse or psychiatric comorbidity (DSM4); 2) medium risk, history of substance abuse or of psychiatric comorbidities (DSM4); 3) high risk, history of dependence and aberrant behavior (theft of prescription, falsification of prescription, injectable use of oral substances, alcohol abuse, aggressively requesting prescription, multiple entries in emergency units, loss of job, family and social life position)^59-61. The chance of developing opioid abuse increases as individuals present more than one risk factor and positive toxicological urine tests are more frequent⁶².

These questionnaires are still not validated in Brazil, have poor psychometric properties and are not reproducible, which implies methodological limitations with no basis for the good clinical practice. In addition, some are complex, extensive and poorly understood by patients. This way, when choosing a tool, one should think about easiness and application time, about physicians' skills to deal with the questionnaire and about patients' clinical characteristics. Self-report tools fail to identify aberrant behaviors⁶³.

Urinary tests may detect the presence of illicit drugs, such as heroin and cocaine, or of other controlled substances not prescribed by the physician. One should remind that 1 out of 5 patients using opioids have positive urinary test with regard to an illicit drug. Urinary tests help detecting substance addiction and abuse in 19.6% of patients. However, they may be false-positive and their use is not a routine⁶⁴.

Treatment of addiction is multidisciplinary, focused on specialized psychological support. Drug therapy includes the use of agonists (buprenorphine or methadone) or of an antagonist (naltrexone). The objective is to prevent or decrease physical dependence, eagerness and relapse and to return all physiological functions (such as sleep and bowel movements) to normal.

One should be careful with the risk of drug interaction, of diversion and overdose potential. Buprenorphine, as opposed to methadone, does not induce electrocardiographic alterations or erectile, cognitive and psychomotor dysfunction. However, its approximate cost is 12 dollars/day and has ceiling effect. Methadone should be started with doses below 40 mg and is the first choice for pregnant patients. However, it poses higher risk for arrhythmia, overdose, weight gain, sedation and relapse after 12 months of treatment. Naltrexone should be started seven days after opioid withdrawal, treating withdrawal syndrome with clonidine. Table 12 shows some drugs to treat addiction⁶⁵.