Why opiates cause miosis

Fasting subjects were admitted to a human volunteer study room where ambient noise and lighting could be controlled and uniform, and complete monitoring, ventilation, and resuscitation equipment and supplies were readily available similar to an intensive care unit or operating room setting. A gauge intravenous line and a gauge radial arterial catheter were placed after an intracutaneous wheal of lidocaine. Initial arterial blood gases were determined and an intravenous remifentanil infusion was begun at a rate of 0.

After 15 min, subjects received a 0. At each 5-min interval thereafter, the continuous infusion of remifentanil was increased by 0. The remifentanil bolus was increased by 0. Two board certified anesthesiologists were available at all times during each volunteer study period, as well as other personnel required for data retrieval.

We measured the following parameters: continuous blood pressure and heart rate from the arterial catheter, additional measure of heart rate and rhythm from a 5-lead electrocardiogram leads II and V5 , fingertip oxyhemoglobin saturation Masimo Corporation, Irvine, CA; set on 2-s rapid response , respiratory rate from both an exhaled carbon dioxide tracing Datex-Ohmeda, Inc.

Arterial blood gases were sampled from the radial arterial line before opioid administration, at the time of oxygen desaturation, and min after recovery. Pupil diameter, pupillary light reflex, and pupil area were measured with an infrared pupillometer Neuroptics, Inc.

The pupillary measures were obtained by using a portable infrared pupillometer. A flash of visible light with an ms duration was delivered at the start of each 3.

The pupillometer calculates the reflex amplitude as the absolute difference between the starting diameter and the minimum diameter obtained after the light flash. The neurological pupillary index NPi is a proprietary tool that displays a unitless numerical value from 0 to 5 indicating the quality of the light reflex. Zero is indexed to represent no light reflex, whereas any measure greater than 3 is considered within the normal range.

Pupillary measurements with large amplitude artifacts brought about by movements of the head or hand are detected by the instrument and labeled as faulty readings. NPi has been used clinically to assess midbrain function based on pupillary parameters, 3 but has not been clinically validated at small pupil diameters after opioid therapy.

During the remifentanil infusion, the volunteers were not stimulated by voice, touch, or prompted to breathe. They were asked to remain quiet and only speak if they had a question or needed assistance. As soon as this endpoint was reached, pupillary measurements were taken, arterial blood gases were obtained, the subjects were aroused by a verbal stimulus if they did not arouse spontaneously, and the remifentanil infusion was discontinued. At min after the discontinuing the infusion, a final arterial blood gas was obtained.

Paired t tests were used to compare differences between the maximal change in pupil diameter to maximal change in the pupillary light reflex. Linear regression was used to determine the relationship between pupil diameter and amplitude of the pupillary light reflex after remifentanil administration. We also examined the correlation between the initial pupil diameter baseline and the change in pupillary diameter between baseline and the size of the pupil at desaturation.

We used TcCO 2 as a surrogate measure of central opioid effect and compared it to pupil diameter and light reflex as other measures of central opioid effect. Because it is known that increased ambient light decreases pupil size linearly until pupil size reaches approximately 3 mm in diameter, 16 we performed a nonlinear fit of change in pupil size versus change in TcCO 2.

Using the change in carbon dioxide allowed us to normalize for the different study subjects and perform nonlinear regression.

Goodness-of-fit to determine the most appropriate nonlinear equation was assessed by plotting residuals and comparing root-mean-square error of other potential fits for both individual subjects and the entire data set.

P value less than 0. Data analysis was performed using JMP Of the 13 subjects enrolled in the study, two refused to continue with the study because of an unpleasant side effect of nausea and vomiting from the remifentanil.

The pupillary data from one subject were contaminated with blink artifacts, so the data from this subject were not used. We therefore present data from the 10 subjects who participated to the end of the study. All measured parameters were significantly altered by oxygen desaturation with remifentanil table 1. Graphic illustration of the changes that occurred in measured variables is shown in figure 2.

In addition to discontinuing the remifentanil infusion, a verbal stimulus reminded the volunteer to breathe time zero on fig. Fractional changes in the measured physiologic parameters at the time of desaturation time zero and during the min recovery phase.

Values are displayed as a fraction of predrug baseline values. Statistical comparisons were only performed between baseline, nadir, and after min of recovery, and the statistical results are summarized in table 1. Note the close correlation between changes in the pupil reflex and pupil area. There was evidence of sympathetic activation of the cardiovascular system with significant increases in heart rate during the progressive desaturation, but parasympathetic effects on the pupil were dominant.

All subjects were noted to have pupillary diameters less than 3 mm at the point of maximal desaturation. Although pupil diameter and area are related by a simple mathematical relationship, we provided both measures in the results because although diameter is a more familiar clinical measure, the flux of light is more directly related to the pupil area.

The quality of the light reflex as assessed by NPi was only minimally altered at all recovery time intervals. As the pupil enlarged during the recovery phase, the light reflex amplitude increased, but NPi at desaturation was only decreased by 6. The light reflexes at each time interval for a single representative individual are shown in figure 3. Example of quantitative pupillary light reflexes obtained by a pupillometer displayed over a 3. The opposite eye was covered with an opaque cloth. A flash visible light was delivered for ms at the start of each scan.

Each line follows the pupil diameter as it changes during the scan. We therefore used the continuous TcCO 2 as a measure of remifentanil-induced respiratory depression as values were continuously recorded and available for all time points of pupillary measure and evaluated the central respiratory effect of increasing opioid as measured by TcCO 2 on pupil diameter fig. After examining several potential fits, including linear, second-order polynomial and bilinear equations, a basic reciprocal form with a parameter for minimal pupil size was the best fit for the data.

The relationship between TcCO 2 and pupil size for all 10 subjects is shown in figure 4A using a nonlinear reciprocal fit. An increase in TcCO 2 was associated with decreasing pupil size.

Regardless of the increase in carbon dioxide, only minimal pupillary change was noted below 3 mm diameter. The nonlinear fit of the data resulted in a minimum pupil diameter corresponding to 2.

Pupil diameters A and pupillary reflex B in relation to transcutaneous carbon dioxide measurements. Individual study subjects are shown with different symbols. Nonlinear reciprocal fits are displayed in each figure. A nonlinear reciprocal fit was also used to evaluate the relationship of decreasing pupillary light reflex with increasing central respiratory depression TcCO 2 , as shown in figure 4B.

In all subjects, the light reflex remained intact and quantifiable using infrared pupillometry. A mean light reflex value of 0. The reciprocal nonlinear fit of the data resulted in a similar value of 0. This is the first study to measure pupillary responses with objective pupillometry during high-dose opioid administration associated with significant hypercarbia and hypoxia. Our primary findings demonstrate that even with opioid doses resulting in severe respiratory depression, the pupil should not be characterized as a dimensionless point i.

These data show that sympathetic activation by hypercarbia and hypoxia overcomes the previously described parasympathetic hemodynamic effects of remifentanil that often include bradycardia and hypotension. Pupillometry in healthy volunteers as a biomarker of tramadol efficacy. Journal of Clinical Pharmacy and Therapeutics, v. Pharmacokinetics, intraoperativeeffectandpostoperative analgesia oftramadol in cats.

Research in Veterinary Science, v. Evaluation of topical nalbuphine or oral tramadol as analgesics for corneal pain in dogs: a pilot study. Veterinary Ophthalmology, v. Accessed: 23, may Opioids are frequently associated to sedatives in the pre-operative period to potentiate the sedative effects of both agents STEPHAN et al.

In cats; however, when associated to tramadol, acepromazine does not act synergistically with regard to tranquilization CASSU et al. Separate neural mechanisms mediate sufentanil-induced pupillary responses in the cat.

Journal of Pharmacology and Experimental Theraputics, v. The pupillary effects of intravenous morphine, codeine, and tramadol in volunteers. Accessed: 07, jan. Miotic and subject-rate effects of therapeutic doses of tapentadol, tramadol, and hydromorphone in occasional opioid users.

Psycopharmacology, v. Comparisonofpupildiameterand tear production in dogstreatedwithacepromazine, tramadolandtheircombination. Revista Ceres, v. Effects of tramadol on tear production, intraocular pressure, and pupil size in dogs: clinical study.

Accessed: 21, jan. Nonetheless, choosing adequate protocols with these purposes may be challenging, once most of analgesic and anesthetic agents change these features TAMURA et al.

Effects of two pre-anesthetic regimens for ophthalmic surgery on intraocular pressure and cardiovascular measurements in dogs. Accessed: 25, Jan. Effects of morphine-alfaloxone-midazolam premedication, alfaloxone induction and sevoflurane maintenance on intraocular pressure and tear production in dogs. Lack of effects of intramuscular medetomidine on intraocular pressure in clinically normal cats.

Journal of Feline Medicine and Surgery, v. Accessed: 13, jan. Previous studies describing the effects of acepromazine and opioids on PD and IOP in this species have not been published so far.

Considering that minimum alveolar concentration of isoflurane is decreased in cats treated pre-operatively with tramadol alone, in addition to the fact that when the agent is associated to acepromazine its anti-nociceptive effects are potentialized CAGNARDI et al. Therefore, the present study aimed to evaluate possible changes in PD and IOP of healthy cats treated with acepromazine, tramadol or the association of both drugs.

Thirty intact domestic short hair cats of both genders 13 males and 17 females , with average weight and age of 3. After the instillation of one drop of 0. Prior to the beginning of the experiment, all individuals were adapted to the procedures and staff for a period of two days. Opioid miosis--that is, pupillary constriction caused by opioids--is one of the most sensitive and frequently assessed objective indices of opioid effects. Pupillary size is also affected by lighting intensity and monocular or binocular exposures.

This study is the first systematic examination and quantitative characterization of the effects of lighting intensity and exposure on opioid miosis. Seven patients received their usual daily dose of methadone mg p.