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A Novel Parenteral NSAID in Acute Pain Management

Dan Carr

 

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Abstract

NSAIDs are widely recommended in acute pain management as single agents or in a multimodal regimen to decrease opioid requirements and side effects. Diclofenac has the highest intrinsic efficacy among nonselective NSAIDs, and a long history of use in acute pain. A novel intravenous (IV) diclofenac formulation (Dyloject™) employs hydroxypropyl beta-cyclodextrin (HPβCD) to solubilize diclofenac in a 2 ml volume that may be administered as a rapid bolus IV injection. This talk will review the current status of Dyloject’s clinical development. An initial single-dose post molar extraction trial (N = 155) showed superior efficacy of Dyloject over the prior IV diclofenac formulation, that contains polyethylene glycol and benzyl alcohol (PG-BA) and requires reconstitution, mixing, and slow (>30 min) infusion of each dose. At 15 min, more patients given Dyloject 75 mg than PG-BA diclofenac 75 mg reported 30% reduction in pain intensity (52% versus 21%, p=0.0022). Both diclofenac products had a 6 hr duration. This trial sufficed for approval of Dyloject in the UK in late 2007; subsequently, formulary acceptance has been high (~90%) and tens of thousands of patients treated uneventfully. An initial dose-ranging US registration trial in molar extraction (N = 353) compared the efficacy and safety of single doses of Dyloject at 5 dose levels, versus IV ketorolac 30 mg and placebo. Dyloject at all doses except 3.75 mg was superior to placebo according to TOTPAR6 (p<0.0001). Dyloject 3.75 mg was statistically superior to placebo for TOTPAR2 and TOTPAR4. Dyloject was superior to placebo (p<0.0001) at the earliest (5 min) assessments of pain relief (18.75, 37.5 and 75 mg) while ketorolac was not. Extraction site bleeding was twice as likely (8.5%) with ketorolac than Dyloject (3.9%). Consistent with prior literature, a subsequent 30-subject study of platelet aggregation showed minimal effect of Dyloject 37.5 mg but marked disruption by aspirin 325 mg or ketorolac 30 mg. Results of the first of two pivotal US registration efficacy trials (N=331 postoperative abdominal or pelvic surgical patients) were recently reported. SPID results (mean mm.hours ± SD) from 0-48 hrs demonstrated that DIC075V 18.75 mg (1262 ± 1092) and 37.5 mg (1521 ± 1112), and ketorolac (1550 ± 984) were all superior to placebo (846 ± 1108, p ≤ 0.017), with no difference between the active treatment groups. Similar results were seen for SPID and TOTPAR over other intervals. Across all trials, Dyloject had a lower incidence of administration site thrombophlebitis than either PG-BA diclofenac or ketorolac. The second US efficacy trial (in post-orthopedic surgical pain) will soon complete accrual. Initial clinical experience with this novel reformulation of a widely used NSAID indicates it is well tolerated and efficacious.

 

Declaration of a conflict of interest:

The author is the CEO/CMO of Javelin Pharmaceuticals, Inc., the manufacturer of Dyloject™

 

Recommended reading

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