To Eliminate The Opiate Vol 2 Pdf

Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal symptoms such as constipation, anorexia, nausea, vomiting, gastro-oesophageal reflux, delayed digestion, abdominal pain, bloating, hard stool and incomplete evacuation that significantly deteriorate patients’ quality of life and compliance. Approximately one third of patients treated with opioids do not adhere to the opioid regimen or simply quit the treatment due to OIBD. Several strategies are undertaken to prevent or treat OIBD. Traditional oral laxatives are used but their effectiveness is limited and they display adverse effects. Other possibilities comprise opioid switch or changing the administration route. New therapies target opioid receptors in the gut that seem to be the main source of OIBD. One is a combination of an opioid and opioid antagonist (oxycodone/naloxone) in prolonged-release tablets, and another is a purely peripherally acting opioid receptor antagonist (methylnaltrexone) available in subcutaneous injections.

• To Eliminate The Opiate Pdf

The aim of this article is to review the pathomechanism and possible treatment strategies of OIBD. Introduction Opioid analgesics are commonly and in most cases effectively used in chronic pain management of moderate to severe intensity.

However, apart from analgesia opioids exert numerous adverse effects which may limit their effectiveness and patients’ compliance. These effects also appear in the gastrointestinal (GI) tract.

Opioid-induced bowel dysfunction (OIBD) is a common adverse effects syndrome associated with the chronic use of opioid analgesics. The OIBD comprises several symptoms including constipation, anorexia, nausea and vomiting, gastro-oesophageal reflux, delayed digestion, abdominal pain, flatulence, bloating, hard stool, straining during bowel movement and incomplete evacuation. In the case of long-term opioid therapy these symptoms may lead to the development of more serious complications such as bowel faecal impaction with overflow diarrhoea and faecal incontinence, pseudo-obstruction (which may cause anorexia, nausea and vomiting), disturbance of drug absorption, urine retention and urine incontinence. Opioid-induced bowel dysfunction may lead to inappropriate opioid dosing and in consequence insufficient analgesia. Opioid-induced bowel dysfunction also significantly deteriorates patients’ quality of life and compliance. Approximately one third of patients treated with opioid analgesics does not adhere to the prescribed opioid regimen or simply quit the treatment due to OIBD symptoms.

Outline of pathomechanism of opioid-induced bowel dysfunction The pathomechanism of OIBD is complex. It seems that the peripheral opioid effect on µ-opioid receptors in the gut wall plays the main role here, but the central effects are also important. High density of µ-opioid receptors was found in neurons of the myenteric and submucosal plexus and immune cells in the lamina propria.

Opioid receptors (predominantly µ, also κ and δ) are located in the gut wall in the myenteric plexus and in the submucosal plexus. The former are responsible for GI motility and the latter for secretion. The µ-opioid receptors are activated in the wall of the stomach and the small and large intestine by both endogenous (e.g. Enkephalins, endorphins and dynorphins) and exogenous (e.g.

Morphine, oxycodone, methadone) opioids and modify GI function. Activation of µ-opioid receptors inhibits excitatory and inhibitory neural pathways within the enteric nervous system that coordinates motility. Inhibition of excitatory neural pathways depresses peristaltic contractions.

On the other hand, the blockade of inhibitory neural pathways increases GI muscle activity, and elevates resting muscle tone, spasm and non-propulsive motility patterns. These mechanisms are responsible for delayed gastric emptying and slowing the intestinal transit. Activation of opioid receptors in the submucosa inhibits water and electrolyte secretion into the gut lumen and increases fluid absorption from the intestine and blood flow in the gut wall. Opioids increase activity in the sympathetic nervous system and thereby decrease the secretion. Endocrine cells located in the epithelium might play a role in regulating motor activity and secretion in the gut. Studies performed in mice indicate that peripheral µ-opioid receptors inhibit the transit independently of central µ-receptors. Moreover, opioids increase ileocaecal and anal sphincter tone and impair the defecation reflex through reduced sensitivity to distension and increased internal anal sphincter tone.

Morphine administration leads to sphincter contraction and to decreased emptying of pancreatic juice and bile , which may cause delayed digestion. Anal sphincter dysfunction is an important factor in the sensation of anal blockage ,. The central mechanism of opioid effects on the GI tract is supported by the results of experimental studies in which intracerebroventricular administration of morphine in rats inhibited gastrointestinal propulsion. This effect was reversed by intracerebroventricular administration of naloxone and vagotomy. Intrathecal administration of morphine reduced gastroduodenal motility and intramuscular morphine gave additional effects. It seems that both central and peripheral opioid effects play a role in opioid GI effects. Indirect evidence of both central and peripheral components of opioid effects on bowel function may be the observed 50-60% response rate to the treatment of OIBD with methylnaltrexone (MNTX), which displays only a peripheral µ-opioid receptor antagonist effect in the treatment of patients with OIBD ,.

Opioid-induced bowel dysfunction is the consequence of reduced GI motility, increased absorption of fluids from the gut and decreased epithelial secretion. The stool remains in the gut lumen for a longer time; therefore, more fluid is reabsorbed and the stool becomes hard and dry. The above effects are also associated with opioids’ inhibition of secretomotor neurons in the epithelium of the gut. Oral and rectal laxatives General measures to be taken in patients with OIBD and constipation include the assessment and application of prophylactic measures matched to the patient's general condition. Change of diet (increased food and fluid intake), more physical activity, sitting position during bowel movement and privacy during the defecation process are recommended. Patients treated with opioids should be considered for prokinetic administration (metoclopramide, domperidone, itopride, prucalopride) ,. Any reversible causes such as hypercalcaemia should also be treated.

Discontinuing or decreasing doses of drugs that may be responsible for development of constipation (e.g. Tricyclics, neuroleptics, anticholinergics) should also be considered.

Patients and families should be educated about the ways of prevention and treatment of OIBD. In the majority of patients with OIBD, laxatives need to be administered. The general recommendation is to combine oral administration of osmotic agents (usually lactulose or macrogol) which have an osmotic effect in the colon with stimulants activating neurons in the myenteric and submucosal plexus in the colon and reducing absorption of water and electrolytes from the intraluminal contents: anthracenes (senna), polyphenolics (bisacodyl) or sodium picosulphate. However, these drugs display limited efficacy in patients suffering from OIBD; moreover, they may cause several adverse effects and must be administered on a regular basis.

Other groups of laxatives are faecal lubricants (liquid paraffin), and stool softeners (surfactants: sodium docusate); however, they are usually ineffective when administered alone. The use of bulk-forming agents such as fibre, bran, methylcellulose and psyllium seeds has a limited role in patients with advanced disease as enough fluids (at least 2 l per day) should be co-administered to avoid intestinal obstruction through viscous mass development in the bowel –. Castor oil is not recommended due to its sudden stimulating effect on bowel motility and the risk of developing strong abdominal cramps. If the oral laxatives are found to be ineffective, rectal treatment is considered. The dose of oral laxatives should be titrated to achieve bowel movement unless adverse effects appear. If there is more than 3 days since last bowel action rectal measures (suppositories e.g. Bisacodyl 10 mg and glycerine 4 g or a micro-enema) may be added to the oral regimen.

Rectal measures may be administered alone in those patients who are unable to swallow oral laxatives and suffer from nausea and vomiting; they might be useful in patients with neurological deficits e.g. Spinal cord compression. Rectal laxatives comprise suppositories increasing intestinal motility through direct stimulation of the nerve endings in the myenteric ganglia of the colon, thus inducing peristalsis (bisacodyl), or using osmotic drugs (glycerol) that act by irritation of the mucosa in the rectum, which also enhances the motility of the colon and subsequently triggers the defecation reflex.

The next step to be taken after these agents are found to be ineffective is rectal enema with normal saline (100-200 ml) or phosphates (120-150 ml). In case of faecal impaction the management depends on the severity of symptoms (rectal pain, abdominal colicky pain, protruding hard faeces and faecal leakage). If the symptoms are not severe in case of soft faeces stimulating agents such as senna or bisacodyl 10-20 mg once daily orally or rectally may be administered until bowel movement is achieved. If hard faeces are present glycerol suppositories or osmotic enemas may be administered. Enema of arachis oil (130 ml) or of decussate sodium (100 ml) may be appropriate. Macrogols reduce the need for digital disimpaction. However, in cases of severe symptoms, when neither oral nor rectal treatment gives a desired effect and faecal impaction is not relieved causing significant distress, it may be necessary to perform digital stool evacuation.

As the procedure is painful and distressing it should be performed with caution. Patients should be sedated with midazolam; for effective pain relief systemic opioids should be given along with topical administration of local anaesthetics. Opioid switch The possibility of opioid switch in the treatment of OIBD should be considered as one of the available treatment options. Opioids which seem to be more often associated with constipation are codeine and dihydrocodeine (opioids for mild to moderate pain), morphine, oxycodone and hydromorphone (opioids for moderate to severe pain). These opioids may be switched to other opioids belonging to the same group but having less constipating effect: codeine or dihydrocodeine may be switched to tramadol; morphine, oxycodone or hydromorphone to transdermal opioids (fentanyl, buprenorphine) or to methadone ,. The most evidence supporting the benefits of the opioid switch as regards constipation relief was accumulated for the morphine to transdermal fentanyl switch –.

Tassinari et al. Performed a meta-analysis comparing 3 randomized trials of transdermal opioids (fentanyl and buprenorphine) with slow-release oral morphine in the treatment of moderate-severe cancer pain in 425 patients. A significant difference in favour of transdermal opioids was observed for constipation (OR = 0.38; p. Targeted treatment of opioid-induced bowel dysfunction Few clinical studies have compared the efficacy of different laxatives , with controlled studies lacking. However, traditional laxatives do not target the cause of OIBD, which is predominantly associated with opioid analgesics binding and activating µ-opioid receptors in the GI tract. If the oral laxatives are found to be ineffective, rectal measures are usually introduced.

Another approach involves treatment directed at the cause of OIBD. This method involves either using a combination of opioid analgesics with opioid receptor antagonists, which act both centrally and peripherally, or administering opioid receptor antagonists, which act exclusively peripherally. An important advantage of this approach is the fact that it is targeted treatment of OIBD and that it may be combined with oral laxatives, if necessary; finally, this approach may eliminate the need for rectal measures, which are poorly tolerated by patients. Apart from opioid antagonists with exclusively peripheral effects, opioid receptor antagonists which also have a central mode of action should be listed: naloxone, naltrexone and nalmefene. The majority of studies performed so far refer to the use of an immediate-release formulation of oral naloxone (IR naloxone). In spite of high IR naloxone efficacy in the treatment of OIBD, in some patients opioid withdrawal symptoms and attenuation of analgesia were observed, rendering IR naloxone less useful when administered alone –. Similar results were obtained in the studies on nalmefene and nalmefene glucuronide.

Combined opioid receptor agonists with antagonists One method to decrease the frequency of constipation in patients requiring strong opioids is to use a formulation composed of an opioid and an opioid receptor antagonist. The formulation combining oxycodone and naloxone is available in the form of prolonged-release (PR) tablets containing both drugs in the ratio of 2: 1 (PR oxycodone/PR naloxone 5 mg/2.5 mg, 10 mg/5 mg, 20 mg/10 mg, 40 mg/20 mg). The optimal 2: 1 ratio of PR oxycodone/PR naloxone tablets was demonstrated in a phase II study rendering effective analgesia and improvement in bowel function with good treatment toleration in patients with severe chronic pain PR oxycodone/PR naloxone is registered for the indication of severe pain which may only be successfully treated with opioid analgesics; naloxone counteracts the development of OIBD through inhibition of oxycodone's effect on opioid receptors in the gut wall. The starting PR oxycodone/PR naloxone doses in opioid-naive patients is 5 mg/2.5 mg b.i.d. Patients unsuccessfully treated with opioids for mild to moderate pain (tramadol, codeine, dihydrocodeine) may start with the dose of 10 mg/5 mg b.i.d. When rotating from other opioids for moderate to severe pain to PR oxycodone/PR naloxone, the starting dose is established individually depending on the amount of previously administered opioid, analgesia and adverse effects. The maximal daily dose of PR oxycodone/PR naloxone recommended equals is 40 mg/20 mg twice daily.

However, in some studies higher daily doses up to 120 mg/60 mg were explored. Following oral administration, oxycodone displays high bioavailability (60-87%) and provides effective analgesia. Naloxone exhibits low bioavailability after oral administration (. Purely peripherally acting opioid receptor antagonists Methylnaltrexone (MNTX) is a derivative of naltrexone, a peripheral µ-opioid receptor antagonist which does not cross the blood-brain barrier. As MNTX has low oral bioavailability it is administered subcutaneously or intravenously and is rapidly absorbed. However, studies in healthy volunteers demonstrated the efficacy of oral MNTX in the prevention of delay in oro-caecal transit time after intravenous morphine administration.

The MNTX plasma half-life equals 105 to 140 minutes, protein binding is approximately 11-15%. Methylnaltrexone is excreted unchanged in 50% to the urine. Methylnaltrexone is a weak CYP2D6 inhibitor with no significant drug interactions. Methylnaltrexone is used in the treatment of opioid-induced constipation in advanced diseases in adult patients when constipation does not respond to conventional oral laxatives. The drug is available in ampoules containing 12 mg MNTX bromide in the volume of 0.6 ml and is applied via subcutaneous injections. A single MNTX dose equals 8 mg in patients with body weight 38-61 kg or 12 mg if the body mass is 62-114 kg. Patients falling outside of this range should receive a dose of 0.15 mg/kg.

In patients with mild to moderate hepatic or renal impairment no dose adjustment is necessary. However, in patients with severe renal failure (creatinine clearance.

To Eliminate The Opiate Pdf

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