Constipation Side Effects of Opioids

subcutaneous methylnaltrexone in adult patients with opioid-induced constipation. One pediatric case series of 15 oncology patients has shown the potential benefi t of subcutaneous methylnaltrex- one in this setting at a mean dose of 0.15 mgkg dose Rodrigues et al. 2013 .

9.4.7.2 Nausea and Vomiting Nausea and vomiting are rare opioid side effects

in children but can occur with therapy initiation and will usually resolve within a few days. If nausea or vomiting persists, antiemetics such as ondansetron can be helpful. A detailed history is necessary to rule out constipation which can be a troublesome side effect of opioid therapy and result in signifi cant nausea and vomiting. Low- dose naloxone has shown potential benefi t in opioid-induced nausea and vomiting Cepeda et al. 2004 ; Maxwell et al. 2005 ; Monitto et al. 2011 .

9.4.7.3 Pruritus Pruritus is a common side effect of opioid use

and is the most common cause of opioid rotation in children Drake et al. 2004 . Pruritus often occurs with opioid initiation and clears within a few days. Low-dose naloxone has shown poten- tial benefi t in relieving opioid-induced pruritus Cepeda et al. 2004 ; Maxwell et al. 2005 ; Monitto et al. 2011 . If not improved with time and low- dose naloxone, opioid dose reduction can be con- sidered. If this is unsuccessful or leads to inadequate pain management, diphenhydramine or hydroxyzine can be used. However, it is impor- tant to recognize that this is not an allergic or histamine-mediated reaction. Opioid rotation should be reserved when the above interventions have not successfully controlled pruritus and pain control is still required.

9.4.7.4 Sedation

Initiation and increase of opioid therapy may lead to a period of drowsiness that typically resolves within a few days. Persistence of seda- tion often is the result of renal, hepatic or CNS disease. In renal dysfunction, one of morphine’s centrally acting metabolites, M6G, can accumu- late. In this example, opioid rotation to an agent not renally excreted such as fentanyl is appropri- ate. Psychostimulants such as methylphenidate have shown benefi t for their role as pain adjuncts and anti-sedatives in adult and adolescent trials but with adverse effects such as decreased appe- tite and tremor Yee and Berde 1994 . These medications have not been studied as an adjunct to opioid analgesia in younger children.

9.4.7.5 Confusion and Agitation Renal and hepatic function should be checked

when children become confused or agitated with opioids, and it should be ensured that correct dos- ing is being given. Opioid doses should be decreased or dosing intervals increased if with underlying hepatic or renal dysfunction. If confu- sion and agitation persist, opioid rotation should be strongly considered.

9.4.7.6 Respiratory Depression When dosed appropriately, opioids rarely result

in respiratory depression Olkkola et al. 1988 ; Lynn et al. 1993 . Cases of respiratory depression have primarily been seen when intravenous opi- oids are rapidly administered for procedures, when there is inability to excrete opioids or with concurrent use of benzodiazepines. Through its release of catecholamines, pain itself acts as a respiratory drive stimulant. Signs to evaluate for true respiratory depression include sleepiness, decreased consciousness, decreased respiratory rate and central apnea. If these symptoms are noted, an opioid antagonist such as naloxone should be administered and opioids restarted at 50 dosing after resolution of symptoms.

9.4.7.7 Myoclonus Patients receiving very high doses of opioids for

a prolonged duration may experience myoclonus. Myoclonus typically presents as brief, involun- tary muscle contractions that occur due to an accumulation of neurotoxic metabolites such as morphine-3-glucuronide M3G. Treatment of myoclonus consists of the use of benzodiazepines such as midazolam or clonazepam or muscle relaxants such as baclofen or dantrolene Mercadante 1998 . Opioid rotation should be strongly considered.

9.4.7.8 Urinary Retention Urinary retention can be caused by any opioid but

is seen more frequently with epidural or spinal opioids, often after rapid dose escalation. Interventions to help treat urinary retention include external bladder pressure, intermittent catheteriza- tion, and bethanechol or tamsulosin to stimulate bladder contraction. However, the easiest and least invasive way to manage this is through opioid rota- tion. Gallo et al. 2008 have shown in adult post- operative patients treated with morphine PCA that low- dose naloxone improved urinary residuals and increased urinary frequency.

9.5 Neuropathic Pain

Neuropathic pain, as described in Sect. 9.3 , is caused by damage to nociceptors and nociceptive pathways leading to abnormal pain signaling. Neuropathic pain has not been well studied in children. Characteristics that make neuropathic pain distressful include underassessment, pro- longed duration and poor response to currently available treatments Simon et al. 2012 . Causes of neuropathic pain include lesions of the spinal cord, tumor-related pain that may damage tissues and nerves, and chemotherapeutic agents such as vincristine see Sect. 9.8.1 , cisplatin, and pacli- taxel. Symptoms can last for months to years and can be exacerbated at the end of life Drake et al. 2003 . Guidelines on assessment and diagnostic scales for evaluation have been designed for adults and can be used in adolescents Haanpaa et al. 2011 . Diagnosis in children is based primarily on symp- tom character and quality see Sects. 9.3 and 9.8.1 . A Cochrane review in adults found mixed results for the use of opioids in the treatment of neuropathic pain Eisenberg et al. 2006 . Adjuvants are typically used with opioids since an effective pain response with opioids alone may not be achieved Chaparro et al. 2012 . Adjuvant medica- tions can cause signifi cant side effects requiring patient and family education about these effects. Systematic evidence on the use of such adjuvant agents in pediatric oncology patients is lacking Jacob 2004 ; Anghelescu et al. 2014 . Additionally, these medications can be used solely but require weeks of gradual titration. Topical agents such as capsaicin and lidocaine have shown some promise in producing analgesia in adult populations Babbar et al. 2009 ; Cheville et al. 2009 .

9.5.1 Calcium Channel Blockers

Calcium channel blockers such as gabapentin and pregabalin bind presynaptic voltage-gated calcium channels in the dorsal horn reducing the release of neuroexcitatory transmitters such as glutamate, noradrenaline and substance P. These agents have been the most studied in the pedi- atric population for neuropathic pain and inhibit the development of hyperalgesia and allodynia Buck 2002 ; Vondracek et al. 2009 . Doses can be titrated upwards as often as every 3 days although side effects may be limiting see Sect. 9.8.1 for dosing. Side effects include lethargy, nausea and vomiting, dizziness, weight gain, and behavioral problems such as aggression, restlessness, and hyperactivity. Gabapentin and pregabalin are renally excreted and doses must be adjusted for renal insuffi ciency or failure.

9.5.2 Serotonin and Norepinephrine

Reuptake Inhibitors SNRIs inhibit serotonin and norepinephrine reuptake and have no effect on postsynaptic receptors. A few adult studies have shown improved neuropathic pain and minimal side effects with these agents Goodyear-Smith and Halliwell 2009 . Nausea is the most common reported side effect. Doses are generally titrated upwards on a weekly basis. Venlafaxine is avail- able in an extended release form.

9.5.3 Tricyclic Antidepressants

The mechanism of action of tricyclic antidepres- sants TCAs is not well understood but appears to result from a combination of serotonin and nor- epinephrine presynaptic reuptake and inhibition