Management of Opioid-Induced Gastrointestinal Effects in Patients Receiving Palliative Care

Abstract
Opioid-induced gastrointestinal side effects, namely, nausea and constipation, are bothersome yet often easy to manage. Due to their widespread frequency, it is imperative that prophylactic and treatment modalities be understood. Although many pharmacotherapeutic agents are available with which to prevent or treat these side effects, few randomized, placebo-controlled studies have been conducted in terminally ill patients, thus limiting most treatment decisions to empiric therapies based on extrapolated data. A strong understanding of the pathophysiology of the sequelae is therefore paramount. Common agents administered for nausea are butyrophenones, pheno-thiazines, metoclopramide, and serotonin-receptor antagonists. Those given to manage constipation are stimulant laxatives and stool softeners, individually or in combination.

Introduction
Nausea and constipation are side effects that may be experienced by terminally ill patients receiving palliative opioid analgesics. The World Health Organization defines palliative care as “the active total care of patients whose disease is not responsive to curative treatment. Control of pain, of other symptoms, and of psychological, social and spiritual problems, is paramount.”[1] This includes patients with cancer but encompasses all terminally ill patients.

Surveys indicate that 50-60% of patients enrolled in hospice programs may experience nausea, constipation, or both, with prevalence rates as high as 40% in the last 6 weeks of life.[2,3] Of these patients, as many as 80% may require an opioid for pain relief.[4] In a study of 260 patients with cancer pain receiving opioids, nausea was rated as moderate to severe in 8.3-18.3%, regardless of the drug. This suggests that patients receiving palliative care frequently experience nausea and constipation, and opioids contribute significantly to these symptoms. It is difficult to determine the exact etiology of these symptoms in the terminally ill population due to other underlying processes such as dehydration, cerebral metastases, and intestinal obstruction. Nausea and constipation may be dose related, with nausea generally subsiding within the first several days after starting therapy. Unfortunately, constipation may remain a constant problem and usually does not abate with continued therapy.[5-9]

Opioid-induced nausea may cause apprehension in patients receiving palliative care. It is estimated that 6-12% of these patients may experience nausea, with some studies reporting its occurrence as high as 29%.[10,11] Often it may be difficult to differentiate the cause of opioid-induced nausea due to various comorbidities, conditions, and concomitant drugs, thus skewing an accurate estimate of its true frequency.[2] Patients often may associate nausea with a recent opioid analgesic, creating potential barriers to effective pain management in the form of anticipatory nausea, anxiety, or adherence problems. Nausea and vomiting may greatly affect patient-reported quality of life scores. In addition, nutrition intake may be limited due to nausea, which also adversely affects quality of life. Constipation, which may be a result of several patient-specific variables, is a large concern and also may adversely affect quality of life. Because the goal of palliative care is symptom management, it is extremely important to understand the symptoms experienced by these patients as a result of prescribed drug therapy.

Due to the paucity of clinical data to guide practitioners in the treatment of opioid-induced gastrointestinal side effects in palliative care, much clinical practice is theoretical, or extrapolated from different patient populations experiencing these symptoms due to different etiologies.

Pathophysiology of Opioid-Induced Nausea
Nausea may be experienced in many conditions, including pregnancy, seasickness, central nervous system (CNS) diseases, anxiety, and opioid therapy. The sensation is orchestrated by a complex group of sensory inputs, ultimately coordinated by the vomiting center in the lateral reticular formation of the medulla (Figure 1). The nausea is experienced depending on which sensory input is stimulated. The vomiting center is stimulated by neurotransmitters, histamine, and acetylcholine. It acts physiologically as a processing center for all the afferent signals that may elicit nausea. Origins of these afferent signals include the chemoreceptor trigger zone (CTZ), vestibular apparatus, and mechanoreceptors and chemoreceptors that originate from various locations in the gastrointestinal tract and cortex.[11-13]

Figure 1. (click image to zoom) Depiction of sensory input to the vomiting center. D2 = D2 dopaminergic; 5-HT3 = serotonin type 3; H1= histamine type 1; Achm = muscarinic acetylcholine. Adapted from reference 9.

The CTZ is located in the area postrema at the floor of the fourth ventricle. Its neurons may be directly stimulated by many toxins, metabolites, or drugs including opioids. Very little barrier exists between systemic circulation and these neurons, which may result in stimulation of the neurons by substances that do not readily cross into CNS circulation.[13] The CTZ also accepts several medullary neurons, which may be responsible for inhibiting the action potential of these specific nerve cells, thus keeping the neurons of the CTZ from firing more readily. Neurons originating from the medulla are hypothesized to be enkephalinergic. It is theorized that displacing them by opioids or opioid antagonists may predispose patients to nausea by, in effect, removing inhibitory input into the CTZ.[12-14]

The vestibular apparatus is located in the bony labyrinth of the temporal lobe and is responsible for detecting changes in equilibrium. By an unknown mechanism, the vestibular apparatus is directly stimulated by most opioids. This may add to the already decreased threshold for nausea these agents cause at the CTZ. The vestibular apparatus provides direct input into the vomiting center by way of cholinergic pathways.[12-14]

Distention of the gut, decreased gastrointestinal emptying time, and constipation may stimulate the mechanoreceptors. Stimulation of visceral mechanoreceptors and chemoreceptors is most commonly responsible for nausea and emesis in terminally ill patients receiving opioid drugs.[12-14] Opioids also decrease gastrointestinal emptying time, which may cause constipation or fecal impaction.[14-19]

Although not as well defined as the other neuronal inputs, the cortex has direct input into the vomiting center through several types of neuroreceptors. A patient may remember unpleasant feelings of nausea associated with past opioid therapy. When presented with the sight, smell, or even anticipation of taking an opioid again, a strong nausea reflex may result.[7,12,20,21]

Treatment
Treatment of opioid-induced nausea is essential. Many practitioners advocate preventive therapy to start with the first dose. Others maintain that this may add another drug, and thus its side effects, to the patient’s prescription profile. Regardless of when treatment is begun, it must be tailored directly to the patient’s history and symptoms. Treatment goals should be realistic and patient oriented. Whereas complete absence of nausea would be preferred, often the goal must be tailored to what the patient feels is tolerable and does not interfere with normal activities. Nausea should be assessed using the same tool at each contact. Often the patient is asked to rank nausea subjectively and volunteers what the goal should be.[22] The agent chosen, regardless of whether it is to prevent or treat nausea, should be easy for the patient to take and without a burdensome side effect profile. With this in mind, the relative lack of randomized, controlled studies often limits drug selection based solely on the practitioner’s knowledge of neurophysiology and pharmacology of available agents.

Reviewing neurotransmitters involved in production of opioid-induced nausea helps elucidate the drug classes used to treat the nausea. The drug classes are butyrophenones, prokinetic agents, phenothiazines, phenothiazine derivatives, antihistamines, anticholinergics, and serotonin (5-HT3) antagonists (Table 1). They may be given as monotherapy or based on response and side effects.[5-9,21,23]

Butyrophenones produce their antiemetic effect by inhibiting the D2 dopaminergic receptor centrally.[24] Haloperidol has potent dopaminergic antagonism at the CTZ. Side effects, including drowsiness, constipation, dystonia, and parkinsonism, are largely dose dependent.[6,10,24] Tardive dyskinesia, torsades de pointes, and neuroleptic malignant syndrome are other adverse effects that may occur with butyrophenones and are considered to be dose independent.

Older persons may be increasingly sensitive to the side effect potential of haloperidol, which includes anticholinergic properties and parkinsonism. This is attributed to age-related decreases in cholinergic and dopaminergic neurons.[25,26] The drugs should not be withheld from patients who may benefit. Haloperidol may be given in dosages of 0.5-2.0 mg 2-4 times/day, and 0.5 mg 2-3 times/day.[27] As preventive therapy for nausea, small dosages of 0.5 mg every 8 hours may be given for the first 2-3 days of opioid therapy.[12] Droperidol tends to be prescribed less frequently than haloperidol for nausea in the palliative care setting largely due to concerns of efficacy and a higher frequency of sedation.

Phenothiazines and derivatives have less dopaminergic antagonism than haloperidol.[12,27,28] Levomepromazine, recently removed from the market in the United States, was an effective antiemetic, probably due to its dopaminergic, anticholinergic, and a1-adrenergic antagonism.[29,30] Caution should be exercised when choosing antiemetics for patients with Parkinson’s disease. Many of these agents may make the disease symptomatically worse by pharmacodynamic drug-disease interaction. Promethazine is relatively well tolerated and has less D2-specific antagonism than other phenothiazines and butyrophenones.[31,32] Anticholinergic side effects and sedation profiles of these drugs may be additive to the comparable side effects of opioids. Anticipating these problems is essential. Chlorpromazine, prochlorperazine, and promethazine are all examples of agents in this class.

Prochlorperazine and promethazine are preferred due to efficacy, side effect profile, and availability in different dosage forms. Prochlorperazine may be administered intra-venously, rectally, or orally; it should not be administered subcutaneously. Dosages range from 5-10 mg every 6-8 hours. Long-acting formulations are available and provide greater simplicity of administration in exchange for higher cost. Promethazine may be administered orally, rectally, intravenously, or subcutaneously. The subcutaneous route often is chosen for palliative care. Dosages of 12.5-25 mg every 4-6 hours may provide relief for patients experiencing mild-to-moderate nausea. Promethazine may not adequately alleviate severe nausea, however.

Metoclopramide is the only prokinetic agent available in the United States. Cisapride is restricted in this country due to drug-drug interactions resulting in fatal cardiac arrhythmias. A less cardiotoxic isomer of cisapride — norcisapride — is in early phases of investigation. Erythromycin has been administered for its prokinetic effects with success; however, its efficacy in treatment of nausea is limited due to its adverse gastrointestinal side effects.[33-36]

Metoclopramide may have several mechanisms of action in this setting.[5,8,20,35,37,38] It produces increased gut transit times through enhancement of acetylcholine response in the gastrointestinal tract.[5,11,12,39] This proves beneficial to patients with nausea associated with constipation. Metoclopramide also inhibits dopamine and serotonin receptors peripherally. In addition, it appears to provide D2-receptor inhibition centrally at high doses (1-1.5 mg/kg/dose).[12] Although metoclopramide is well established in the treatment of nausea, parkinsonism may be experienced, especially when prescribed at dosages required for dopaminergic activity. It is available orally and parenterally and may be administered intravenously or subcutaneously. Dosages frequently range from 5-10 mg every 4-6 hours, although 120 mg/day was reported.[5] This agent often is considered first-line therapy for opioid-induced nausea due to its side effect profile and mechanisms of action.[5,27,38]

Serotonin receptor antagonists ondansetron, granisetron, and dolasetron are potent antiemetics. Serotonin receptors have been isolated in the CTZ as well as the vomiting center.[12-14] Although typically administered to prevent and treat cancer chemotherapy- and radiotherapy-induced nausea, these agents may be efficacious in the treatment of opioid-induced nausea.[6,8,9,40,41]

Single doses of ondansetron 8 mg, 16 mg, or placebo were administered to 520 subjects with pain sufficient to require opioid analgesia.[41] Nausea was abated completely in 6.8% of subjects receiving placebo, 14.8% of those receiving ondansetron 8 mg, and 19.4% of those receiving ondansetron 16 mg. Ondansetron 8 mg was not significantly different from placebo; however, the 16-mg dose did show a statistically significant difference (p=0.007). Whereas these agents hold promise in opioid-induced nausea, they are costly and should not be considered first-line therapy.

Antihistamine and anticholinergic antiemetics are widely used in palliative care due to efficacy and decreased cost. The histamine antagonists are active at the vomiting center as well as the vestibular apparatus, which makes them valuable in the treatment of nausea associated with movement or vertigo.[19,42] Anticholinergic drugs are also excellent antiemetics due to their inhibition of acetylcholine directly at the vomiting center.[12,43] Side effects may be bothersome (e.g., xerostoma, constipation, blurred vision, confusion), but at low dosages the drugs are generally well tolerated and may be administered in combination with other antiemetics to expand coverage of various etiologies of nausea. Hyoscine, in contrast to other anticholinergics, may have limited value in the treatment of nausea due to lack of central activity.[12] Transdermal scopolamine is effective for patients experiencing swallowing difficulty; however, relief may not be experienced for several hours due to absorption delay associated with percutaneous delivery.[12,43]

Corticosteroids may be of utility. Although the mechanism of action is not understood, several theories exist, including reduced blood-brain barrier permeability to offending agents and depletion of central amine gamma-aminobutyric acid (GABA) in inhibitory medullary neurons projecting into the CTZ (this in turn would increase excitability of the inhibitory neuronal projections).[5,12,14,44] Dexamethasone is the most widely studied corticosteroid in adjunctive treatment of nausea; however, few data exist addressing its efficacy in opioid-induced nausea.[5,20,44-49]

A randomized, double-blind study compared dexamethasone with placebo for treatment of opioid-induced nausea.[44] Seventy-four patients undergoing total abdominal hysterectomy who received epidural morphine sulfate were randomized to one of two groups: dexamethasone 8 mg intravenously or normal saline in the same volume. Both dexamethasone and placebo were administered as single doses immediately after surgery, and total vomiting and nausea scores were assessed for 24 hours. The total frequency of nausea and vomiting between dexamethasone and placebo groups was significantly different (16% and 56%, respectively, p0.05) in hard stool frequency or defecation frequency, although both agents were superior to placebo