Ventilatory Effects of Ketorolac and Morphine in Chronic Obstructive Pulmonary Disease

ORIGINAL RESEARCH ARTICLE

Drug Inves\. 5 (I): 1-10. 1993 0114-2402/93/0001-0001/$05.00/0 © Adis International Limited. All rights reserved.

DRI1164

Ventilatory Effects of Ketorolac and Morphine in Chronic Obstructive Pulmonary Disease

Sammy C. Campbell, I Peter Krumpe 2 and John Shepard 3 I Veterans Administration Hospital, and Department of Internal Medicine and Division of Respiratory

Sciences, University of Arizona, Tucson, Arizona, USA 2 Veterans Administration Medical Center, Martinez, California, USA 3 Mayo Clinic, Sleep Disorders Center, Rochester, Minnesota, USA

Summary Ketorolac (ketorolac-tromethamine) is a non-narcotic drug with an analgesic efficacy com-parable with that of narcotic agents in postoperative pain. This single-dose single-blind randomised multicentre crossover study evaluated the ventilatory effects of intramuscular ketorolac 30mg and intramuscular morphine IOmg in 34 patients with mild to moderate stable chronic obstructive pulmonary disease. Patients had a screening visit (no drug) for baseline spirometry and 2 follow-up visits, I week apart, at which they received either morphine or ketorolac. Assessments of ventilatory response to hypercapnia were made before drug administration and hourly for 4 hours after administration at each of the 2 follow-up visits. At each hourly assessment there were statistically significant decreases in mean minute ventilation and mean inspiratory flow after morphine but not after ketorolac. Significantly more patients reported adverse effects after morphine than after ketorolac. The absence of ventilatory depression and improved tolerability indicates an advantage of ketorolac over morphine in the treatment of postoperative pain.

Patients with chronic obstructive pulmonary disease (COPD) are known to have a depressed ventilatory response to carbon dioxide (C02) [Tenney 1954]. That this response is caused by the obstructive defect itself, rather than by chronic resetting of the respiratory drive, as once assumed (Cherniack & Snidal 1956), is confirmed by measurements demonstrating that central respiratory drive is normal in patients with CO PO even when ventilatory response is decreased (Gelb et aL 1977). Narcotic drugs such as morphine, pethidine (meperidine), fentanyl and others, which are frequently used for postoperative pain control, can cause significant ventilatory depression even in normal subjects (Budd 1981; Mueller et aL 1982; Olson et aL 1986). This effect is potentially a more serious concern in patients with lung disease.

Ketorolac (ketorolac-tromethamine) is an effective non-narcotic analgesic agent of the nonsteroidal anti-inflammatory class of drugs (NSAIDs). Studies of ketorolac in the treatment of postoperative pain have shown that an intramuscular (1M) dose of 30mg is comparable in analgesic efficacy with 1M morphine sulphate 12mg or pethidine IOOmg. The onset of action is comparable with that of narcotic agents, but the duration of action is longer, up to 6 hours (Estenne et aL 1988; O'Hara et aL 1987; Yee et aL 1986). The respiratory depression associated with narcotic drugs has not been observed after administration of ketorolac in clinical trials, and therefore this drug may have a significant advantage in treating patients with COPD who require pain medication.

2

This study was designed to evaluate the effects of 1M ketorolac 30mg and 1M morphine 10mg on ventilation in patients with mild to moderate stable COPD, by assessing both the ventilatory response (as measured by minute ventilation) and the central respiratory drive (as reflected in inspiratory flow). The hypothesis tested was that in these patients morphine, but not ketorolac, would depress the central respiratory drive and decrease the ventilatory response to C02.

Methods

The single-dose randomised crossover study was conducted at 3 centres. Neither the patients nor the technicians who measured ventilatory response knew the sequence in which study drugs were administered. All patients had mild to moderate stable COPD characterised by a clinical diagnosis of emphysema or chronic bronchitis, a spirometric pattern consistent with airway obstruction (ACCP Committee on Pulmonary Physiology 1967; Morris et al. 1984), and a serum theophylline concentration of:::; 20 mg/L on each day of testing and differing by no more than 3 mg/L between the 2 test days. Patients with the following characteristics were excluded from the study: chronic or recent acute C02 retention (PaC02 > 45 torr); a history of active peptic ulcer within 6 months, recent head injury, increased intracranial pressure, hypothyroidism, Addison's disease, symptomatic prostatic hypertrophy, or urethral stricture; a history of hypersensitivity or adverse reaction to any narcotic, salicylate or NSAID, or of recent anticoagulant use; any clinically significant abnormality on haematological or biochemical screening. Patients gave informed written consent and the study protocol was approved by the institutional review boards.

Ketorolac was provided by Syntex Laboratories (Palo Alto, California, USA) in single-dose ampoules containing 30mg of drug in 1 ml of solution, each labelled with the study, patient and week number. Patients were assigned at random to receive by 1M administration either ketorolac 30mg followed a week later by morphine lOmg, or mor-

Drug Invest. 5 (1) 1993

phine 10mg followed a week later by ketorolac 30mg. Doses used were those considered appropriate on the basis of previous studies of treatment for moderate to severe pain; the interval between doses was set at I week to ensure an adequate washout period.

After a screening visit (visit 1) at which no study drug was given, each patient returned for 2 study visits, I week apart (visits 2 and 3), and received either morphine or ketorolac, as assigned. Spirometry was performed at all 3 visits. At visits 2 and 3, spirometry was carried out before administering study medication and at the conclusion of the 4-hour study period. Assessments of ventilatory response to carbon dioxide were made prior to administration of study medication (pretreatment) and hourly for 4 hours postdose at visits 2 and 3 (post-treatment). Pretreatment ventilatory response measurements provided baseline scores for each treatment. Post-treatment measurements were analysed as change in scores by subtracting baseline scores from each hourly post-treatment score. At each visit, patients were asked to describe any adverse effects occurring during the prior week.

Mean forced expiratory volume in I sec (FEV 1) scores were computed by averaging 2 measurements (between which the difference was not> 15% of the larger value); these scores were expressed as a percentage of the predicted scores based on normal values for age and height (ACCP Committee on Pulmonary Physiology 1967; Morris et al. 1984). The ratio of the mean FEV 1 and forced vital capacity (FVC) was calculated for each patient and expressed as a percentage of the predicted ratio.

Ventilatory responses to hyperoxic hypercapnia were measured by the rebreathing method of Read (1967) with modifications to measure inspiratory flow and volume. Patients breathed a gas mixture of 50% 02, 43% N2, and 7% C02 maintained until the system was closed to test the response to hypercapnia. For each assessment, the response to hypercapnia was measured over 4 minutes of rebreathing. During the last 3.5 minutes of rebreathing, end-tidal C02 (PETC02)' minute ventilation eVe), inspiratory time (Tj), and tidal volume (Vt )

were averaged for the first 3 breaths of every 20-

Ventilatory Effects of Ketorolac and Morphine in COPD

second interval. The Ve and mean inspiratory flow (Vt/Ti) were each plotted against PETC02' Best fit least squares regression lines for Ve vs PETC02 and Vt/Tj vs PETC02 were determined and the Ve and Vt/Tj values at a Pco, of 55 torr were estimated from these regression lines. The slopes of the Ve vs

PETCO, and the Vt/Tj vs PETC02 regression lines and the estimates of Ve and Vt/Tj at a PC02 of 55 torr were the ventilatory response measurements of interest.

The slopes of the regression lines that plot the relationships between Ve and end-tidal C02 tension (PETC02)' and between mean Vt/Tj and PETC02' have traditionally been used to indicate the magnitude of ventilatory response, since a steeper slope of this line (i.e. a higher numerical value) reflects a greater response to rising C02 levels (Read 1967). In this study, ventilatory responses were analysed at a PC02 value of 55 torr because these measurements reflect shifts in the response that may not be reflected by changes in slope. Ventilatory responses at PC02 values from 55 to 60 torr have previously been reported in normal subjects (Peterson et al. 1981; Whitelaw et al. 1975) and in patients with lung disease (Altose et al. 1977; DiMarco et al. 1983; Plotkowski et al. 1987; Scano et al. 1986), and have been used to assess the effects of pharmacological agents (Campbell et al. 1981).

For FEV 1, FEV l/FVC, and ventilatory response measurements, a 3-way repeated measures analysis of variance was applied, with 'visit' as the repeated variable for pretreatment responses. Post-treatment ventilatory responses (visits 2 and 3, hourly for 4 hours after drug administration) were evaluated from hourly change scores using 3-way repeated measures ANOV A with 'treatment' as the repeated measure, an extension of the crossover analysis of variance procedure described by Grizzle (1965). Nonparametric Wilcoxon tests based on procedures derived by Koch (1972) were also used.

McNemar's test with Yates' continuity correction for the significance of changes was used to test for differences in the proportion of patients who reported adverse events after receiving I drug but not after receiving the other. When the adverse

3

Table I. Summary of demographic data for the 30 patients analysed for ventilatory response

Age (years) Mean (± SEM) 61.0 ± 1.8 Range 36-83

Height (em) Mean (± SEM) 175 ± 1.02 Range 160-188

Body mass index (%)a Mean (± SEM) 116.6 ± 2.6 Range 76.7-143.8

Raee (no. of patients) Caucasian 28 (93%) Black 2 (7%)

Gender Male 30 (100%)

a Body mass index is the ratio of actual weight to 'ideal weight" for height and sex. The computation was: body mass index (% of ideal) = (100) [weight (kg)]/height [m]2 (22.1) [Kantor 1989].

Abbreviation: SEM = standard error of the mean.

event frequency for each drug was too small for McNemar's test, a binomial test was used.

Results Patients

Three investigators enrolled a total of 34 patients, all of whom were included in the safety analyses. Four were excluded from ventilatory response analyses because of protocol violations: 3 after receiving ketorolac [I patient whose mean FEV 1 values differed by 25% between visit I (screening) and visit 2, I patient who did not return for the last visit, and I patient whose theophylline concentrations differed between visits 2 and 3 by more than 3 mg/L); and I after receiving morphine (concomitant chlordiazepoxide administration). Thus, data from 30 patients were included in the ventilatory response and spirometry analyses. The demographic data are presented in table I.

Pretreatment results of spirometry and measurement of serum theophylline concentrations are

4 Drug Invest. 5 (I) 1993

Table II. Pretreatment spirometry and theophylline concentrations. and ventilatory responses at visits 2 and 3 in patients with chronic

obstructive pulmonary disease prior to receiving intramuscular ketorolac 30mg or morphine 10mg

Visit 2 Visit 3 Test results p

K M K M comparison statistics8

No. of patients 14 16 16 14

FEV1 (OJ. predicted) Mean 52.39 56.10 56.00 54.12 Seq F(1.24) = 2.85 0.10

SEM 1.75 2.62 2.60 2.29 Inv F(2.24) = 1.85 0.18

Minimum 41.36 38.72 42.84 40.82 Seq x Inv F(2.24) = 4.11 0.029

Maximum 64.31 77.14 79.58 68.41 Visit F(1.24) = 0.10 0.76

FEV1/FVC (OJ. predicted) Mean 80.0 77.0 76.1 80.7 Seq F(1.24) = 0.14 0.72

SEM 3.4 3.1 2.9 3.6 Inv F(2.24) = 5.06 0.015


Maximum 102.5 99.3 99.2 102.9 Visit F(1.24) = 0.00 0.96

Theophylline (gIL) Mean 7.2 7.6 7.6 7.5 Seq F(1.22) = 0.01 0.92

SEM 1.2 1.5 1.5 1.3 Inv F(2.22) = 2.28 0.13


Maximum 15.0 15.0 14.5 15.0 Visit F(1.22) = 1.94 0.18

Minute ventilation slope (L/min/torr) Mean 2.24 2.50 2.36 2.05 Seq F(1.24) = 0.37 0.55

SEM 0.24 0.36 0.30 0.19 Inv F(2.24) = 0.85 0.44


Maximum 3.50 7.10 5.00 3.00 Visit F(1.24) = 0.57 0.46

Minute ventilation at PETCO, = 55 torr (LIm in) Mean 35.95 38.48 41.51 38.85 Seq F(1.24) = 0.12 0.73

SEM 4.58 3.65 3.01 5.45 Inv F(2.24) = 5.05 0.015 Minimum 10.78 20.39 21.00 6.14 Seq x Inv F(2.24) = 2.63 0.09 Maximum 68.20 82.00 70.00 81.70 Visit F(1.24) = 1.35 0.26

Mean inspiratory flow slope (L/min/torr) Mean 5.71 6.20 5.93 5.68 Seq F(1.24) = 0.15 0.70

SEM 0.61 0.78 0.72 0.52 Inv F(2.24) = 0.38 0.69


Maximum 8.60 16.10 11.50 8.10 Visit F(1.24) = 0.14 0.71

Mean inspiratory fiow at PETCO, = 55 torr (L/min) Mean 96.13 101.57 106.48 104.51 Seq F(1.24) = 0.00 1.00

SEM 11.71 8.35 7.33 14.16 Inv F(2.24) = 3.92 0.034 Minimum 31.38 48.00 51.00 24.81 Seq x Inv F(2.24) = 1.68 0.21

Maximum 165.20 187.00 160.00 211.90 Visit F(1.24) = 1.25 0.27

a Three-way repeated measures analysis of variance was used with 'visit' as the repeated measure. Between-patient comparisons for treatment sequence. investigator. and sequence-by-investigator (Seq x Inv) interaction are shown. as well as within-patient

visit comparisons. Abbreviations: K = ketorolac; M = morphine; SEM = standard error of the mean; FEV1 = forced expiratory volume in 1 sec;

FVC = forced vital capacity; PETCO, = end-tidal C02; seq = sequence; inv = investigator.


shown in table II. There were no significant differences between values obtained at the 2 treatment visits.

Post-Treatment Pulmonary Function

A comparison of combined data from both treatment visits revealed no significant differences in FEV I or FEV I/FVC ratio between pre- and posttreatment values (table III). Similarly, ventilatory response measurements performed before treatment with study drug showed no differences between treatment groups or between study days (table II).

For each of the hourly assessments of ventilatory response to hypercapnia during the 4-hour post-administration period (visits 2 and 3), statistically significant treatment difference·s were found between groups in Ve and Vt/Ti at PETC02 = 55 torr (table IV, fig. 1). After administration of ketorolac, the means of both of these measures remained essentially unchanged, while after morphine each decreased. The post-treatment slopes of

Ve VS PETC02 and Vt/Ti vs PETC02 decreased more after administration of morphine than after ketorolac (table V, fig. 2). The treatment differences between these slopes approached statistical significance at-2 (p = 0.051) and 3 (p = 0.088) hours.

2.4

.,

.~ -;:- 2.2

5 B ~ ~ 2.1 c:_ al ..J > - 2.0 ~ :> c: ~ 1.9

a

o 2

Time (h)

3 4

5

Table III. Spirometric measurements in patients with chronic obstructive pulmonary disease receiving intramuscular ketorolac 30mg or morphine 10mg

Ketorolac Morphine

No. of patients 30 30

Pretreatment FEV1 (% predicted) Mean 54.31 55.18 SEM 1.62 1.74 Minimum 41.36 38.72 Maximum 79.58 77.14

Post-treatment changeS in FEV1 (% predicted) Mean -0.93 -2.47

SEM 1.89 1.57 Minimum -32.57 -30.89 Maximum 17.58 11.03

Pretreatment FEV1/FVC (% predicted) Mean 77.92 78.73 SEM 2.21 2.34 Minimum 55.81 46.57 Maximum 102.53 102.93

Post-treatment change in FEV1/FVC (% predicted) Mean -0.68 -1.76 SEM 1.65 1.42 Minimum -26.98 -25.89 Maximum 17.37 9.13

a Post-treatment value minus pretreatment value. Abbreviations: See table II.

b

o 2

Time (h)

3 4

Fig. 1. Minute ventilation (~e) [a] and mean inspiratory flow (Vt/Tj) [b] treatment means at PC02 = 55 torr in 30 patients with chronic obstructive pulmonary disease receiving intramuscular ketorolac (e) or morphine (0) in a crossover design. A comparative analysis of change from baseline scores showed significant differences between ketorolac and morphine treatments at all time points [p ~ 0.0008 (a) and p ~ 0.0016 (b)]. PETCO, = end-tidal C02.

Table IV. Change in minute ventilation (L/min/torr), and post-treatment mean inspiratory flow (L/min/torr) at PETCO, = 55 torr in patients with chronic obstructive pulmonary I 0-

disease receiving intramuscular ketorolac 30mg or morphine 10mg

Change in minute ventilation Post-treatment mean inspiratory flow

ketorolac morphine comparison ANOVAa Wilcoxonb ketorolac morphine comparison ANOVAa Wilcoxonb

(L/min/torr) (L/min/torr) p p (L/min/torr) (L/min/torr) p p


Mean 38.91 38.65 Seq 0.77 0.79 101.65 102.94 Seq 0.98 0.72

SEM 2.67 3.14 Inv 0.01 6.67 7.83 Inv 0.03

Minimum 10.78 6.14 Treatment 0.93 0.37 31.38 24.81 Treatment 0.71 0.77

Maximum 70.00 82.00 Visit 0.26 0.47 165.20 211.90 Visit 0.27 0.77

Post-treatment changeC

1 hour Mean 0.89 -7.07 Seq 0.98 0.98 2.90 -16.46 Seq 0.42 0.66

SEM 1.12 1.43 Inv 0.24 2.15 3.30 Inv 0.21

Minimum -14.57 -22.30 Treatment 0.0008 0.0003 -17.60 -43.40 Treatment 0.0001 0.0003


2 hours Mean 1.40 -8.79 Seq 0.95 0.88 1.16 -17.91 Seq 0.86 0.69

SEM 1.16 1.20 Inv 0.58 4.10 2.95 Inv 0.29



3 hours Mean 0.22 -10.73 Seq 0.047 0.06 3.26 -21.58 Seq 0.58 0.31

SEM 1.43 1.09 Inv 0.040 3.06 2.59 Inv 0.19



4 hours Mean -1.10 -10.30 Seq 0.75 0.63 -0.36 -22.23 Seq 0.77 1.00

SEM 1.15 1.03 Inv 0.25 3.12 2.87 Inv 0.27


Maximum 15.93 3.70 Visit 0.59 0.30 57.52 14.00 Visit 0.76 0.83 t1 ... ~ ..... ;:,

a Analysis of variance (ANOVA) with treatment as the repeated measure was used. The sequence factor is a pretest for a carryover effect. For the pretreatment analysis, ~ the treatment factor is equal to the visit-by-sequence interaction. For post-treatment analyses, the visit factor is equal to the treatment-by-sequence interaction. v. b The Wilcoxon test statistic p values are based on the non parametric procedures derived by Koch (1972). --. c Change in value at 55 torr, post-treatment value minus pretreatment value. -:::

..... Abbreviations: See table II. '0

'0 ....


a 45

o 2 3 4

~ 6.0 o iii

t; 5.8 G ~F 2 g 5.6

~ .~ 0_ "§ ~ 5.4 '5. I/)

.!: c: '" Q)

~

Time (h)

5.2

7

b

o 2 3 4

Fig. 2. Minute ventilation (~cl [a) and mean inspiratory flow (Vt/Tj) [b) slope treatment means in 30 patients with chronic obstructive pulmonary disease receiving intramuscular ketorolac 30mg (e) or morphine 10mg (0) in a crossover design. A comparative analysis of change from baseline scores showed no significant difference between ketorolac and morphine treatments at any time point [p ;;. 0.11 (a) and p ;;. 0.051 (b)) .

Adverse Effects

One patient in the ketorolac-morphine sequence, after receiving morphine, withdrew prematurely from the study because of nausea, diaphoresis and dizziness. After administration of morphine, 27 of 32 patients reported 1 or more adverse effects; IO of the 34 patients who received ketorolac reported I or more adverse effects following this treatment. 19 patients reported I or more adverse effects after receiving morphine but not after receiving ketorolac, while only I patient reported adverse effects after receiving ketorolac but not after receiving morphine (p < 0.001). The 2 most frequently reported adverse events were dizziness/lightheadedness and gastrointestinal (GI) upset. After administration of morphine, 13 patients reported dizziness/lightheadedness and IO reported GI upset. After ketorolac, 2 patients reported dizziness/lightheadedness and 2 reported GI upset. These differences between the treatment groups were statistically significant (p < 0.003 and p < 0.039, respectively).

Discussion

Postoperative analgesia is frequently inadequate, largely because insufficient doses of narcotic

agents are administered to reduce side effects such as respiratory depression (Melzack 1990; Parkhouse et al. 1961). Alternative approaches have been proposed, including the wider use of non-narcotic analgesics such as the NSAIDs, either alone or in combination with narcotic agents (Hug 1980; Kontor 1989; Levine 1984; Stimmel 1985). The availability of an injectable NSAID with strong analgesic activity and a favourable safety profile offers an important alternative to current analgesic therapy. Clinical trials with ketorolac have established the efficacy and safety of this drug in treating postoperative pain (Estenne et al. 1988; O'Hara et al. 1987; Yee et al. 1986).

The ventilatory depressive characteristic of narcotic agents is thought to be related to /-L-opioid receptor activity within the central nervous system. The /-L receptors are considered to be the principal receptors responsible for pain relief and respiratory depression (Stimmel 1983). The ventilatory response to breathing C02 is a time-honoured method of evaluating the respiratory effects of centrally acting drugs (Bellville & Seed 1960; Forrest & Bellville 1964), and remains a useful tool for defining the actions of sedative and analgesic agents on the respiratory centre (Olson et al. 1986; Pleuvry et al. 1980; Skatrud et al. . 1990). An earlier study using this methodology demonstrated that ketorolac did

Table V. Post-treatment minute ventilation slope (L/min/torr) and mean inspiratory flow slope (L/min/torr) in 30 patients with chronic obstructive pulmonary disease I 00

receiving intramuscular ketorolac 30mg or morphine 10mg

Post-treatment minute ventilation slope Post-treatment mean inspiratory flow slope

ketorolac morphine comparison ANOVA" Wilcoxonb ketorolac morphine comparison ANOVA" Wilcoxonb

(L/min/torr) (L/min/torr) p p (L/min/torr) (L/min/torr) p p


Pretreatment Mean 2.30 2.29 Seq 0.56 0.92 5.83 5.96 Seq 0.72 0.98 SEM 0.19 0.21 Inv 0.44 0.47 0.47 Inv 0.68 Minimum 0.30 0.93 Treatment 0.79 0.63 1.00 1.84 Treatment 0.35 0.71 Maximum 5.00 7.10 Visit 0.46 0.37 11 .50 16.10 Visit 0.71 0.82

POlt-treatment changeC

1 hour Mean -0.10 -0.24 Seq 0.98 0.97 -0.19 -0.32 Seq 0.72 0.55 SEM 0.13 0.13 Inv 0.59 0.28 0.34 Inv 0.63 Minimum - 2.50 -1.70 Treatment 0.24 0.62 -5.00 -5.40 Treatment 0.22 0.66 Maximum 1.20 1.70 Visit 0.10 0.28 2.40 5.10 Visit 0.23 0.98

2 hours Mean -0.09 -0.32 Seq 0.60 0.92 -0.19 -0.61 Seq 0.53 0.39 SEM 0.13 0.13 Inv 0.13 0.35 0.31 Inv 0.57 Minimum -2.40 -2.50 Treatment 0.23 0.16 -4.90 -4.68 Treatment 0.051 0.42 Maximum 1.20 0.94 Visit 0.65 0.60 5.10 2.80 Visit 0.79 0.74

3 hours Mean -0.17 -0.44 Seq 0.40 0.21 -0.36 -0.86 Seq 0.64 0.39 SEM 0.13 0.11 Inv 0.36 0.34 0.35 Inv 0.71 Minimum -2.40 -1.80 Treatment 0.11 0.17 -5.50 -5.00 Treatment 0.088 0.27 Maximum 1.00 0.52 Visit 0.30 0.28 3.50 3.48 Visit 0.31 0.78

4 hours Mean -0.19 -0.34 Seq 0.65 0.30 -0.41 -0.53 Seq 0.57 0.18 SEM 0.13 0.11 Inv 0.37 0.28 0.36 Inv 0.53 Minimum -2.40 -1 .90 Treatment 0.39 0.37 - 4.70 -4.62 Treatment 0.27 0.78 t1 ... Maximum 1.00 0.70 Visit 0.29 0.17 2.40 3.00 Visit 0.43 0.78 ~ ....

;:"

a Analysis of variance (ANOVA) with treatment as the repeated measure was used. The sequence factor is a pretest for a carryover effect. For the pretreatment analysis, ~ the treatment factor is equal to the visit-by-sequence interaction. For post-treatment analyses. the visit factor is equal to the treatment-by-sequence interaction. v.

b The Wilcoxon test statistic p values are based on the non parametric procedures derived by Koch (1972). ....... -::: c Change in value at 55 torr, post-treatment value minus pretreatment value. ...... Abbreviations: See table II. '0

'0 .....


not cause respiratory depression in normal volunteers (Brandon Bravo et al. 1986). The present trial was designed to investigate the possible respiratory effects ofketorolac as compared with those ofmorphine in patients with COPD. It is important to define the effects of these agents in this patient population because patients with COPD are at high risk for respiratory complications because of impaired ventilatory function.

In this study, morphine significantly decreased the ventilatory response to hypercapnia in patients with COPD, while ketorolac had no effect. At PETCOz = 55 torr, decreases in minute ventilation and mean inspiratory flow of approximately 20 to 25% occurred following morphine administration, while these parameters were essentially unchanged after ketorolac treatment. The differences between these drug effects were highly statistically significant. The results are comparable with the effects reported in subjects without lung disease (Brandon Bravo et al. 1986). Both the present and earlier studies show that ketorolac administration does not lead to the respiratory depression that may follow the administration of morphine and other narcotic agents. Thus, the risk to the patient and the requirement for close monitoring associated with narcotics may be minimised with ketorolac use, and better analgesia may be provided. Also, in the present study ketorolac was associated with significantly fewer adverse events than morphine.

Conclusion

The combination of proven analgesic efficacy, absence of a ventilatory depressive effect, and a lower rate of adverse events indicates an advantage for ketorolac over narcotic agents in the control of postoperative pain.

Acknowledgement

The authors thank Drs Carol A. Francisco and James P. Young for statistical analysis, Geraldine Howitt for technical assistance in the laboratory work, and Dr Daniel Liberthson for editorial assistance. This work was supported in part by a grant from Syntex Laboratories, Inc., Palo Alto, California, USA.

9

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Drug Invest. 5 (lj 1993

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Correspondence and reprints: Dr s.c. Camphell, Department of Veterans Affairs, Pulmonary Section, Tucson, AZ 85723, USA.

Documents

Ventilatory Effects of Ketorolac and Morphine in Chronic Obstructive Pulmonary Disease