Ocular Transmucosal Absorption and Toxicity of Sufentanil in Dogs (1998)

The search for an optimal method to control breakthrough cancer and postoperative pain is ongoing. Many routes of analgesic drug administration have been used, including sublingual, nasal, transdermal, and oral transmucosal [1]. Delivering pain medication via topical application to the eye could provide a rapid, convenient, and cost-effective treatment for breakthrough pain. Ocular administration is an attractive alternative for patients who do not tolerate the oral route because of nausea, and it is less noxious than intranasal administration and more acceptable than rectal administration in many patients. Sufentanil is a very potent opioid with widespread clinical availability. It has a relatively high lipophilicity and should be rapidly absorbed after topical administration to the conjunctiva of the eye. However, the absorption and bioavailability of sufentanil (or other opioids) has not been determined after topical ocular administration. In this study, we attempted to determine whether the ocular application of sufentanil could produce significant plasma concentrations within a short period of time. Additionally, we examined whether the topical administration of sufentanil caused any detectable ocular toxicity. Methods Approval for this study was granted by our institution's animal care and use committee. Dogs were selected as the study animal because the size of their conjunctival sac allowed the administration of an adequate volume of sufentanil. Five dogs weighing an average of 27 kg were studied. Each dog received telazol 75 mg intramuscularly at the onset. An intravenous (IV) catheter was then placed in the forepaw and 500 mL of lactated Ringer's solution was given. The femoral artery was cannulated for hemodynamic monitoring and blood sampling. The dogs each received 3 mg of pancuronium and were tracheally intubated. Anesthesia was maintained initially using a 1% end-tidal concentration of halothane. Halothane levels were then adjusted to keep the mean arterial pressures between 60 and 100 mm Hg. The dogs were mechanically ventilated, with periodic arterial blood gas samples measured to ensure that normocarbia was maintained. The lead II electrocardiogram was continuously monitored for each dog. Commercially available sufentanil (50 micro g/mL, pH 3.5-6.0) was used for the study. A total of 50 micro g (1 mL) of sufentanil was delivered over 2.5 min to one eye in each dog in 100-micro L aliquots using a micropipet. Blood samples were obtained at 0, 2.5, 5, 7.5, 10, 12.5, 15, 20, 30, 40, 50, 60, 90, 180, and 240 min after the start of sufentanil application. Plasma concentrations of sufentanil were determined by using a radioimmunoassay (Research Diagnostics, Inc.). A single sample was used for each measurement. The initial dog's radioimmunoassays were run separately. The other four dogs' assays were run together at a later time. Ocular toxicity related to sufentanil application was determined by using two methods. First, an ophthalmologist performed direct ophthalmoscopic evaluation of the anterior segment of each eye before administering sufentanil, and again at the conclusion of the study. The indices examined included: conjunctival injection, conjunctival discharge, limbal vasculature, corneal opacity, extent of corneal opacity, aqueous cells, aqueous flare, iris vasculature, and posterior synechiae. At the conclusion of the study (240 min), each dog was killed using intravenous potassium chloride while anesthetized. The eyes were harvested by an ophthalmic pathologist for histopathologic evaluation. The globes were examined grossly, then sectioned, processed, and stained with hematoxylin-eosin for microscopic evaluation. The ophthalmic and pathologic evaluations were completed without knowledge as to which was the study eye. The ophthalmic pathologist believed that acute inflammatory changes induced by an eye drop should be seen at the 4-h time of death. Results Five dogs were used to obtain data in this study. Mean +/- SD plasma sufentanil concentrations at each sampling time are shown in Table 1. The mean plasma sufentanil concentrations at 5, 7.5, and 10 min were 810 +/- 526 pg/mL, 602 +/- 571 pg/mL, and 564 +/- 458 pg/mL, respectively. Plasma sufentanil levels declined to 76 +/- 90 pg/mL by 50 min. One dog showed a significant second peak in plasma sufentanil level at 15-20 min. This was not the dog whose radioimmunoassays were run separately.Table 1: Sufentanil Plasma Concentration in Five DogsAll of the dogs remained hemodynamically stable throughout the 4-h study period, as determined by monitoring electrocardiogram, arterial pressure, and arterial blood gas measurements. Inspired halothane concentrations between 0.6% and 2.0% were required to keep the mean arterial pressure 60-100 mm Hg. Data was obtained from all five dogs for the entire 240-min period. Direct ophthalmoscopic examination did not show any significant differences between the study and control eyes in any of the dogs, neither at the beginning nor at the end of the study period. The only difference noted was a very slight increase in conjunctival injection, only one of the nine variables studied, in the eye receiving sufentanil in one dog. All other indices (conjunctival discharge, limbal vasculature, corneal opacity, extent of corneal opacity, aqueous cells, aqueous flare, iris vasculature, posterior synechiae) were unchanged and did not differ between study and control eyes. Gross and light microscopy was performed on both study and control eyes in all five dogs. No significant signs of inflammation or toxicity were noted on gross or microscopic evaluation of the globes. Similarly, complete histopathologic evaluation of the globes using light microscopy revealed no signs of ocular inflammation or toxicity. Discussion The ideal method for treating breakthrough pain in cancer patients has yet to be found. IV, intramuscular, epidural, intrathecal, sublingual, nasal, transdermal, and oral transmucosal routes have all been used. The IV, epidural, and intrathecal routes are invasive and expensive to place and maintain. In addition, these routes have been associated with constipation, urinary retention, respiratory depression, and serious infection. The delivery of analgesic medication by topical application to the eye offers many attractive properties. It does not require the medical personnel for administration, nor an invasive catheter. It also avoids oral administration in a patient population that may not be able to take oral medication. The occurrence of a biphasic peak in the plasma sufentanil level in one of the dogs is concerning if repeated use in humans is an eventual therapeutic goal. This could have been due to delayed absorption from distal gastrointestinal tract or a laboratory measurement error. Redistribution of sufentanil from the muscle compartment back into the plasma, as is sometimes seen with shivering and on emergence from anesthesia, seems unlikely because the dog was anesthetized and not moving at the time of the second peak. Study in a larger number of animals is required to address this issue. Sufentanil is an especially attractive drug for ocular administration because its potency and lipophilicity allow for a significant dose to be given in a small volume. The analgesic serum concentration for postoperative pain relief in humans has been determined to be in the range of 0.01 to 0.56 ng/mL [2]. Our study found that a mean peak plasma concentration of 0.81 ng/mL was achieved in only five minutes in a dog model. This plasma concentration is well above the range known to be analgesic in humans. Also inviting in regard to potential clinical application is that the plasma concentrations reliably decreased to low levels within 50-60 minutes. Human studies are necessary to determine whether these levels are approachable, and if so, whether there would be excessive sedation, respiratory depression, or chest wall rigidity. These are important clinical questions, given the fact that there is no known threshold plasma sufentanil level for muscular rigidity. No evidence of ocular inflammation or toxicity was found on ophthalmoscopy or pathologic evaluation of the eyes. Sufentanil seems to have potential as a treatment for breakthrough pain via ocular application. These results encourage more work to be done to evaluate the long-term safety and efficacy of topical ocular sufentanil.