Vincristine-Related Peripheral Oncology-Specifi c Pain

Gabapentin and opioid agents have been used to treat vincristine-related neuropathic pain alone or in combination. Gabapentin, in doses ranging from 10 mgkgday up to 50–70 mgkgday, was well tolerated and reduced pain scores amongst children undergoing ALL treatment Anghelescu et al. 2011 . Studies from adult patients with peripheral neuropathy from other causes have shown that coadministration of gabapentin with opioids resulted in signifi cantly better pain control than placebo or either agent alone Gilron et al. 2005 . This synergistic effect was also observed in rat models Matthews and Dickenson 2002 . Prior to gabapentin, TCAs were considered fi rst-line therapy for neuropathic pain and can be considered see Sect. 9.5.3 Sindrup and Jensen 1999 . Mouse models implicating 5-HT2A recep- tor involvement in neuropathic pain have led to interest in the use of SNRIs though clinical evi- dence in humans is lacking Marchand et al. 2003 ; Thibault et al. 2008 . Case reports have discussed use of pyridoxine and pyridostigmine with some effect but larger case series or trials have not been performed Akbayram et al. 2010 . Other chemo- therapeutic agents linked to neuropathic pain syn- dromes include other vinca alkaloids vinblastine, vinorelbine, platinum agents cisplatin, oxalipla- tin, taxanes paclitaxel, docetaxel and newer agents like bortezomib Han and Smith 2013 .

9.8.2 Osteonecrosis

Osteonecrosis ON is a painful and potentially crippling condition typifi ed by ischemic and necrotic changes in bone. In children, ON is com- monly associated with corticosteroid exposure in ALL and lymphoma but can occur independent of steroid therapy in cancers involving bone or bone marrow Vora 2011 . Additional risk factors for ON include age 10 years, obesity, Caucasian race, treatment intensity and asparaginase use Mattano et al. 2000 ; Niinimaki et al. 2007 ; Kawedia et al. 2011 . While many children treated for ALL have evidence of ON on mag- netic resonance imaging MRI, symptomatic ON incidence is 20 Mattano et al. 2000 ; Kawedia et al. 2011 ; Hyakuna et al. 2014 . Pain from ON ranges from mild intermittent pain to chronic debilitating pain. Analgesic treat- ment for ON should follow the general guide- lines of the WHO pain ladder see Sect. 9.4.1 starting with NSAIDs, if appropriate. COX2 inhibitors such as celecoxib may be preferable in patients for whom antiplatelet effects are a con- cern. Intermittent short-acting opioids may be suffi cient for patients who cannot tolerate NSAID therapy. Patients with persistent pain requiring multiple doses of opioids per day benefi t from long-acting opioids. In patients with chronic pain, methadone is an attractive option given its resistant nature to opioid tolerance. Patients who develop chronic pain from ON may best be served by a chronic pain management specialist. Bisphosphonate therapy has been recently investigated as a method for reducing pain in patients with ON. An Australian study risk strati- fi ed a small population of children with ON and found reduction in pain amongst “severe risk” patients who received monthly IV pamidronate versus “moderate risk” patients receiving oral bisphosphonates and “mild risk” patients receiv- ing calciumvitamin D supplementation Kotecha et al. 2010 . A Canadian study similarly found that 1417 77 patients with symptomatic ON noted pain relief with a 3-day course of IV pami- dronate given every 4 months Leblicq et al. 2013 . A study investigating zoledronic acid in children has demonstrated similar results Padhye et al. 2013 . Referral to an orthopedic surgeon experienced in ON management can be benefi cial, especially for patients with signifi cant debilitating symptoms. Surgical options which can improve functionality and reduce pain include core decom- pression and joint replacement. Other suggested supportive care measures for ON include physical therapy, weight loss, and treatment of vitamin D defi ciency, if present Vora 2011 .

9.8.3 Post-lumbar Puncture

Headache Lumbar puncture LP is a common diagnostic and therapeutic procedure in pediatric oncology. Although relatively uneventful, the most common adverse effect of LP is a post-procedure headache. Typically occurring within 72 h of the procedure, symptoms of post-LP headache include throbbing pain in the bilateral occipital and frontal regions that is exacerbated by vertical position and Valsalva and palliated by lying fl at. Most head- aches resolve within 7 days, but some last for sev- eral weeks. The headache is thought to be caused by leakage of cerebrospinal fl uid CSF and sub- sequent loss of CSF pressure. It is theorized that loss of CSF pressure leads to traction on pain- sensitive intracranial structures or an increase in cerebrovascular blood volume with resultant vasodilation, either of which could cause head- ache Turnbull and Shepherd 2003 . In children, the incidence of post-LP headache has been reported to be between 6 and 15 and has been shown to occur in even young children although is much more common in adolescents Kokki et al. 1999 ; Lee et al. 2007 ; Crock et al. 2014 . Various methods have been proposed to reduce the occurrence of post-LP headache. General guidelines suggest that LP performed with cutting needles should have the beveled edge oriented parallel to the dural fi bers, which run longitudi- nally Janssens et al. 2003 . Post- procedure bed rest has been suggested, but not found to be help- ful Lee et al. 2007 . Studies investigating the use of smaller gauge needles have not found signifi - cant differences in incidence Ebinger et al. 2004 ; Crock et al. 2014 . Use of an atraumatic, or “pen- cil-tip,” needle i.e., Whitacre, has been shown to signifi cantly reduce the incidence of post-LP headache although one study found no difference Kokki et al. 1999 ; Thomas et al. 2000 ; Apiliogullari et al. 2010 . When a post-LP headache occurs, various methods have been employed to treat pain not responsive to NSAIDs or opioids. Oral and IV caffeine has been most widely studied in adults and shown to reduce pain when compared to placebo Sechzer and Abel 1978 ; Camann et al. 1990 . It is hypothesized that caffeine causes relief by decreasing cerebrospinal pressure via cerebrovascular vasoconstriction Janssens et al. 2003 . Dosing of caffeine ranges from 300 to 500 mg in adult studies Lee et al. 2007 ; Basurto Ona et al. 2011 . The effectiveness of caffeine has not been reported in pediatrics, but dosing has been suggested at 100 mg for chil- dren aged 6–10 years and 200 mg for children 10 years McGhee et al. 2011 . In studies with small sample sizes, gabapentin and the combi- nation of caffeine and ergotamine have been shown to reduce pain measured on a visual ana- log scale when compared with placebo Dogan 2006 ; Erol 2011 . Hydration, although men- tioned in supportive care for post-LP headache, has not demonstrated effectiveness when stud- ied Janssens et al. 2003 ; Lee et al. 2007 . A Cochrane review concluded that there is no evi- dence that sumatriptans are effective Basurto Ona et al. 2011 . Severe post-LP headache refractory to medi- cal management can be treated with an epidural blood patch EBP. The procedure involves obtaining access to the epidural space in the area of the previous LP. The patient’s peripheral blood, obtained under sterile technique, is then inserted into the epidural space. The purpose of the procedure is to create pressure to seal the dural tear and prevent further CSF leakage Turnbull and Shepherd 2003 . Kokki and col- leagues 2012 reviewed 41 cases of EBP proce- dures in children and found that 90 had immediate and complete pain relief, with 85 noting permanent relief. In pediatric oncology, blood patches should be considered cautiously given infectious risks for immunosuppressed patients and the theoretical risk of introduction of tumor cells into the CSF.

9.8.4 Mucositis Pain

Pathogenesis and management of mucositis is discussed in Chap. 11 . General pain practices described here are necessary interventions for patients experiencing oral mucositis.

9.9 Summary

The large majority of pediatric oncology patients will suffer from pain at some point during their treatment course secondary to the underlying