Introduction
Pruritus is an unpleasant sensation of the skin provoking a desire, even an urge, to scratch. The origin of the word “pruritus” comes from the Latin word prurire. It is also known as itching(2,3).
Opioid-induced pruritus (OIP) is not a life-threatening condition, but it may have a major impact on one’s quality of life, by affecting sleep and causing anxiety or depression. These symptoms in turn may decrease the patient’s satisfaction and compliance with the proposed opioid therapy and, as a result, in an increase of the healthcare costs(4,5).
Incidence of opioid-induced pruritus
Various factors, such as the type, the dose and the route of administration of the opioid drug, along with individual sensitivity could affect the incidence of OIP. Some articles mentioned pregnancy as a potential favoring factor for opioid-induced pruritus, most likely resulting from an interaction between estrogens and the opioid receptors(6-8). The literature mentions an incidence of OIP anywhere between 2% to 20% after oral administration, 10% to 50% after intravenous administration, and 30% to 100% after neuraxial administration(4,7).
An article stated that the incidence of opioid-induced pruritus related to morphine could be at about 65% to 70% after the epidural administration and at about 62% to 85% after the intrathecal route. The percentages tend to run high as well for sufentanyl (around 55% with epidural and 80% with intrathecal delivery) or for fentanyl (67% after epidural use and 67% to 100% after intrathecal administration)(9). However, another article mentioned that the highest prevalence (up to 100%) was associated with intrathecal morphine(10).
The frequency of opioid-induced pruritus rises with increasing opioid dosages(8,10).
There are data showing that the risk for OIP in parturient patents could be anywhere between 60% and 100% after neuraxial delivery, and that it is related to the dose of the opioid used. The postulated mechanism is, as previously mentioned, a possible interaction of estrogens with the opioid receptors(9).
Mechanisms of opioid-induced pruritus
The mechanism of OIP is not yet fully understood, but most likely more than one pathway may be involved in producing this disturbing opioid side effect(4,7).
Multiple hypotheses aiming to explain the mechanisms of OIP have been proposed in literature:
1. Centrally mediated process via µ-opioid receptors with a possible presence of an “itch center” or of an activation of the medullary dorsal horn or of an antagonism of inhibitory transmitters(8-11).
2. Mast cells activation with subsequent histamine release that could be triggered by systemic or neuraxial administration of some opioids such as morphine, hydromorphone, codeine or meperidine(1,9). One article recommended using oxycodone, oxymorphone or fentanyl, drugs that could cause less histamine release(12).
3. 5-HT3 receptors activation after neuraxial administration of opioids, based on the presence of a dense concentration of serotonin receptors in the dorsal part of spinal cord and the nucleus of the trigeminal nerve in the medulla(9).
4. Release of prostaglandins (PGE1 and PGE2), known to untie histamine from the mast cells and to potentiate pruritus induced by histamine. The same prostaglandins enhance C fiber transmission to the central nervous system. This theory may explain the antipruritic effects of nonsteroidal anti-inflammatories (NSAIDs)(9).
5. Opioid antagonism of the neurotransmitters gamma-aminobutyric acid and glycine in the central nervous system(7,9).
6. Stimulation of dopamine D2 receptors that could explain the use of droperidol(10).
An article indicated that the pruritus associated with opioids is most likely an adverse effect rather than an allergic reaction(13).
Intensity of opioid-induced pruritus
The severity of OIP varies from mild to severe, with one article mentioning that about 50% to 60% of the patients may require treatment or hospitalization after the administration of morphine epidurally(7).
Topography of opioid-induced pruritus
Usually, the pruritus related to spinal or epidural administration of opioids tends to spread cephalad from the site of injection, at the face and upper thorax, whereas pruritus after the intravenous administration could be also localized in the facial area but it could as well be of a generalized type. This topographic distribution of the OIP could be explained by the fact that the dorsal part of spinal cord and the trigeminal nerve nucleus are areas with a high density of both mu-opioid and serotonin 5-HT3 receptors(7).
Transmission of OIP sensation
The pruritic sensation received from the free nerve endings in the skin is transmitted by the unmyelinated C fibers and myelinated A delta fibers to the central spinothalamic tract(1).
Treatment of opioid-induced pruritus
Several treatment options have been proposed based on the aforementioned mechanisms for opioid-induced pruritus.
1. µ opioid receptor antagonists
Opioid antagonists are the recommended treatment option for OIP, according to multiple articles; however, their usage is limited due to reports of decreased analgesia(10).
A) Naloxone
Naloxone is a synthetic derivative of oxymorphone that antagonizes all the µ, k and d opioid-receptor sites and, as a result, it was approved for the reversal of opioid overdose and for the reversal of respiratory depression resulting from the therapeutic opioid use in children and adults. Its onset of action occurs within 2 minutes after the intravenous administration and after 2 to 5 minutes after the subcutaneous, intramuscular and other parenteral routes of administration. It has a short duration of action, 30 to 60 minutes, depending on the dose and the route of administration(4,7,8).
The recommended dose of naloxone hydrochloride for adults for a total reversal of opioid overdose is 0.4-2 mg, repeated every 2 to 3 minutes, to a maximum dosage of 10 mg intravenously, whereas the dose for the reversal of an opioid-induced respiratory depression is 0.1-0.2 mg repeated every 2 to 3 minutes, as needed in an intravenous bolus(8).
However, when trying to address the opioid-induced pruritus, the clinician should employ a low enough dose of naloxone to reverse only the pruritus and not the analgesic effect of the opioid. For this purpose, the research recommended a continuous infusion of naloxone, because it produces less fluctuation of naloxone concentrations compared to the bolus injections and also compensates for the relatively short half-life of the naloxone(4,8).
The dose of naloxone in a continuous intravenous infusion, by which the incidence of OIP could be decreased by approximately 25%, should be 0.25-2 mcg/kg body weight/hour. The naloxone dose should not exceed 2 mcg/kg body weight/hour to prevent the reversal of analgesia(4). A “piggyback” continuous infusion of naloxone at a dose of 0.25 to 1 mcg/kg/hour was also recommended by the National Comprehensive Cancer Network (NCCN) in its guidelines for adult cancer pain(8).
B) Naltrexone
Naltrexone is an oral opioid receptor antagonist and an analogue of naloxone, approved in 1984 by the US Food and Drug Administration (FDA) for the treatment of alcohol, heroin and opioid addiction. It has a longer half-life (4 hours versus less than 60 minutes) and twice the potency of naloxone. The recommended initial dose is 25 mg orally followed by a maintenance dose of 50 mg daily(8,14).
C) Methylnaltrexone
Methylnaltrexone is a derivative of naltrexone developed for the treatment of opioid-induced constipation in patients with advanced illness. It has a decreased ability to cross the blood-brain barrier and, like other peripherally acting mu opioid receptor antagonists (POMARAs), it targets the peripheral opioid-binding sites in the gastrointestinal tract. As a result of its limited activity on the central µ-opioid receptors, it may have a limited or no effect on the centrally mediated pruritus(8).
D) Nalmefene
Nalmefene is an opioid antagonist used primarily in Europe for the management of alcohol dependence and investigated for the treatment of other addictions, such as pathological gambling. At doses of 15-25 mcg, nalmefene was found to decrease the need for antiemetic and antipruritic medications(4).
2. Mixed agonist-antagonist opioid receptors
A) Nalbuphine
Nalbuphine is a synthetic, mixed agonist-antagonist opioid analgesic developed for the control of moderate to severe pain. It has an activating effect on the kappa opioid receptors which are known to antagonize the effects of the mu-receptors at central and peripheral levels and, as a result, nalbuphine was indicated off-label for the prevention and treatment of opioid-induced pruritus(4,6,11).
Nalbuphine at doses of 10 mg intravenously induces analgesia with less respiratory depression compared to the mu-receptor agonists, and at lower doses, of 3 or 5 mg intravenously, it has been shown to address the opioid-induced pruritus more effectively than naloxone or propofol(6,7).
Other studies revealed nalbuphine being superior to propofol in the prevention of OIP. A prospective double-blind study compared propofol 20 mg with nalbuphine 3 mg after intrathecal morphine following caesarean delivery. The treatment was significantly more successful in the nalbuphine group than in the propofol group (83% versus 61%, respectively; p<0.001)(4).
Nalbuphine – either as an intermittent injection, or as a low-dose admixture to mu-opioid agonist infusions – emerges as a potential first-line treatment of opioid-induced pruritus when comparing the relief of pruritus with effects on analgesia and sedation(6).
B) Butorphanol
Butorphanol is a mixed kappa-opioid receptor agonist and a mu-opioid receptor antagonist that was approved by the FDA for the management of pain severe enough to require an opioid analgesic and for which the alternative treatments are inadequate. Several studies have shown that butorphanol could decrease opioid-related pruritus when administered epidurally with morphine or in combination with bupivacaine and morphine. Other studies, however, mentioned the fact that butorphanol itself can induce pruritus. It is recommended to monitor the patients receiving butorphanol in combination with any CYP3A4 inhibitors or inducers and it is to be avoided in patients younger than 18 years of age(4,15).
3. General anesthetics
Propofol
Propofol is known to cause a marked depression of posterior horn transmission in the spinal cord and, as a result, a decrease in the severity of opioid-induced pruritus(10).
Several studies using subhypnotic doses of propofol administered prophylactically have shown a decrease in the incidence of pruritus following intrathecal or epidural administration of morphine. The doses used in two such studies were 10 mg bolus followed by a continuous infusion of 30 mg/24 h in one study versus a single dose of propofol 20 mg in another one(4).
A prospective, randomized, double-blind, placebo-controlled study looked at OIP after the administration of 10 mg of propofol in patients who have received morphine intrathecally during gynecological, orthopedic, thoracic or gastrointestinal surgeries. The propofol group had a significantly higher success rate compared with placebo (84% versus 16%, respectively; p<0.05)(4).
However, two studies showed that subhypnotic doses of propofol did not relieve the pruritus in women who underwent caesarean section and received intrathecal morphine sulfate for postoperative pain relief(10).
In addition, propofol may transiently cause hypnosis in postoperative patients(4,9,10).
4. Serotonin 5-HT3 receptor antagonists
Ondansetron
Several studies investigated the efficacy of ondansetron in relieving opioid-induced pruritus, based on the known fact that dense concentrations of serotonin receptors are present in the dorsal part of spinal cord and in the nucleus of the spinal tract of the trigeminal nerve in the medulla(3,9). The results were controversial, with some studies showing good response from ondansetron and others showing no benefit(10).
There was a randomized placebo-controlled study investigating ondansetron 4 mg intravenously or 8 mg sublingually versus placebo in male patients receiving intrathecal morphine that showed a decreased incidence of OIP with ondansetron, regardless of the way of administration, compared with placebo(4).
Another placebo-controlled randomized study looked at ondansetron 4 mg intravenously in patients who received intrathecal morphine for post-caesarean section analgesia. The study showed that ondansetron relieved OIP (80% versus 36% success rate, p<0.001), particularly in patients with nausea and vomiting in addition to pruritus(4,7).
5. Dopamine D2 receptor antagonists
Droperidol
Droperidol is a potent antagonist of the dopamine D2 receptors which has also a weak anti-5-HT3 activity(3,10).
A randomized study by Horta et al. explored the effectiveness of the prophylactic administration of intravenous droperidol 1.25 mg compared to placebo and also of alizapride 100 mg, propofol 20 mg and promethazine 50 mg in reducing the incidence and severity of OIP after neuraxial opioid administration in 300 women undergoing caesarean section. The study showed the opioid-induced pruritus having the lowest prevalence in the droperidol subgroup compared to placebo or to the propofol or alizapride subgroups(4,10,16).
Another study looked into a group of 40 patients who underwent hip replacement and noticed that OIP was significantly diminished in the subjects who received epidural droperidol(10).
6. Histamine H1 receptor antagonists
H1 receptor blockers may alleviate the peripherally generated OIP, but they have little or no effect on the centrally induced one. It is suspected that the antihistamines – particularly the first-generation group – may be effective in reducing pruritus mostly due to their sedative effects since sleep interrupts the itch-scratch cycle(3,7,10).
A placebo-controlled trial by Juneja et al. concluded that hydroxyzine 50 mg administered intramuscularly was effective in attenuating the incidence of severe opioid-induced pruritus in 40 patients requiring epidural morphine for postoperative pain relief(17).
However, another study found that promethazine 50 mg was ineffective in preventing OIP(4).
7. Nonsteroidal anti-inflammatories
The NSAIDs may help with opioid-induced pruritus by blocking the release of prostaglandins (PGE1 and PGE2), a fact demonstrated by several studies. It was proven in a study that 20 mg of intravenous tenoxicam was effective in reducing pruritus after epidural fentanyl, and 100 mg of diclofenac intrarectally decreased morphine-induced pruritus in another study. The results have not been promising with celecoxib, a cyclooxygenase 2 isoenzyme inhibitor(3,10).
Conclusions
In conclusion, opioid-induced pruritus is a common side effect of the opioids, especially after the neuraxial administration, with unclear mechanisms of action and with still conflicting data regarding the efficacy of various treatments.
Conflict of interests: The authors declare no conflict of interests.