Tramadol chocolate oral formulation: pharmacokinetics and tolerability

INTRODUCTION
Pain specialists are frustrated by the limited availability of approved potent analgesics for children undergoing surgery and
cancer therapy. Tramadol, a centrally acting codeine analog with less potential for abuse and a better safety profile than
oxycodone, is prescribed widely for treating moderate and severe pain in adults
1
. Several clinical trials have shown tramadol
to be effective and safe in managing paediatric pain2
, however, none of the 63 registered tramadol products in Australia is
recommended for use in children3
. Off-label use of tramadol is met by manipulating the capsule products into powder or liquid
doses4
, which expose the highly bitter tramadol leading to poor therapy adherence. This study is a pilot, single-centre, open
label, randomized clinical study to evaluate the pharmacokinetic parameters and taste tolerability of a novel chocolate based
drug delivery system (CDS) of tramadol against the standard of care comparator liquid formulation.
METHOD
Children aged 3-16 years independently prescribed tramadol for pain control prior to surgery at the Perth Children’s Hospital
(PCH) and whose parent/guardian had provided informed written consent were recruited. Exclusion criteria were known allergy
to tramadol, opioids or the CDS ingredients, on medications or had medical conditions contraindicated to tramadol. A 5-point facial hedonic scale was applied to assess taste tolerability. Blood samples were taken using a sparse venous blood sampling approach. Plasma tramadol and O-desmethyltramadol were quantified using validated reversed phase high performance liquid chromatography. Population pharmacokinetic parameters were determined using the non-linear mixed effects modelling
(NONMEM) software. The study was approved by the PCH and university ethics committees.
RESULTS AND DISCUSSION
Analysis of taste scores (score of 1-5, with 5 indicating high acceptance) showed mean scores of 3.82 for the tramadol CDS tablet (n=65) and 2.01 for the comparator (n=70), the difference was statistically and clinically significant (Table 1). About 78% of children in the CDS group indicated a willingness to take the same formulation again, compared to only 35% from the comparator group. Analysis of plasma tramadol concentrations from 134 participants showed the bioavailability (BA) of the
CDS tablet to be 1.42 times higher than for the oral comparator (95% CI of 1.29 – 1.55, %RSD 4.49). The relative BA of the CDS tablet was adjusted to 1.16 (95% CI of 1.06-1.26, %RSD 4.51), i.e. similar to the comparator, after it was determined that the comparator had lower than expected drug concentration - 4.08 mg/ml or 81.64% of labelled strength due to the method of preparation. No significant adverse events were noted for both tramadol CDS tablet and comparator liquid in the clinical trial.
CONCLUSION
The novel CDS tramadol tablets have favourable taste tolerability and non-inferior bioavailability relative to the standard of care liquid comparator.