ORIGINAL CONTRIBUTION codeine; hydrocodone
Hydrocodone Versus Codeine in Acute Musculoskeletal Pain Study objectives: To evaluate the efficacy and prevalence of side effects of hydrocodone versus codeine in acute pain syndromes. Type of participants/setting: Sixty-two consecutive adult emergency department patients 18 to 70 years old with acute musculoskeletaI pain. Patients using other analgesics or having any contraindication to opioid therapy were excluded. In addition, 12 patients were excluded because of insufficient data or study dropout. Design/interventions: In a randomized, double-blind prospective manner, patients received either 5 mg hydrocodone with 500 mg acetaminophen or 30 mg codeine with 500 mg acetaminophen to take on discharge from the ED and every four hours thereafter as needed for pain. Measurements: Pain intensity was evaluated by a visual analog scale .at zero, one, two, four, eight, 24, and 48 hours. Specific side effects were sought, along with the number of patients reporting inadequate analgesia. Main results: Data were obtained on 50 subjects (25 per group). Mean and median pain scores did not differ significantly at time zero (x vs y, 6.03 vs 5.99 and 6.8 vs 6.1, respectively) or subsequent intervals. Side effects were noted in eight hydrocodone/acetaminophen and 18 codeine/acetaminophen patients (P = .005). No significant differences in gastrointestinal side effects were reported; however, less nausea or vomiting was reported in the hydrocodone group (P = .23). Central nervous system side effects (sedation or lightheadedness) were reported in six hydrocodone/ acetaminophen patients compared with 16 codeine/acetaminophen patients (P < .005). In addition, no hydrocodone/acetaminophen patients reported inadequate analgesia compared with six codeine/acetaminophen patients (P < .05). Conclusion: Although pain scores were not significantly different, hydrocodone may be a more effective analgesic than codeine in acute muscuIoskeletaI pain, as demonstrated by significantly fewer treatment failures. Central nervous system side effects are less common with hydrocodone than with codeine. [Turturro MA, Paris PM, Yealy DM, Menegazzi JJ: Hydrocodone versus codeine in acute musculoskeletai pain. Ann Emerg Med October 1991;20:1100-1103.]
INTRODUCTION Patients presenting to emergency departments often require acute pain management. Although several oral narcotic agents exist, little scientific data are available comparing their relative efficacies or the prevalence of side effects. Therefore, physicians choose agents largely on the basis of familiarity and drug company promotion. Codeine remains the most often prescribed oral narcotic analgesic.t Hydrocodone bitartrate, another schedule III agent, is a codeine congener that has been used since 1920 for its analgesic and antitussive properties. Early studies in the German literature suggested that 5 mg hydrocodone is equianalgesic to 30 mg codeine, z Because combining a narcotic analgesic with a non-narcotic analgesic such as aspirin or acetaminophen augments the analgesic potential, a drug companies have most often marketed these agents in combination preparations in which various amounts of acetaminophen are added to either codeine (Tylenol 3 ®) or hydrocodone (Anexsia ®, Co-Gesic ®, Vicodin ®, Zydone®). Codeine is usually prescribed in ei-
20:10 October 1991
Annals of Emergency Medicine
Michael A Turturro, MD*¢§ Paul M Paris, MD, FACEP¢¢ Donald M Yealy, MDt¢II James J Menegazzi, PhD$ Pittsburgh, Pennsylvania Temple, Texas From the University of Pittsburgh Affiliated Residency in Emergency Medicine;* Division of Emergency Medicine, University of Pittsburgh;¢ The Center for Emergency Medicine of Western Pennsylvania;¢ and The Mercy Hospital of Pittsburgh, Pittsburgh, Pennsylvania;§ and Division of Emergency Medicine, Texas A&M University College of Medicine, Temple, Texas.II Received for publication July 20, 1990. Revision received February 20, 1991. Accepted for publication March 21, 1991. Presented at the Scientific Assembly of the American College of Emergency Physicians in San Francisco, September 1990. Funding for this study was provided by The Center for Emergency Medicine of Western Pennsylvania and Central Pharmaceuticals. Address for reprints: Michael A Turturro, MD, Department of Emergency Medicine, The Mercy Hospital of Pittsburgh, 1400 Locust Street, Pittsburgh, Pennsylvania 15219.
1100/71
HYDROCODONE VS CODEINE Turturro et al
ther a 30-rag or 60-mg dose and hydrocodone in either a 5-rag or 7.5-rag dose. P h a r m a c e u t i c a l companies have also p r o m o t e d h y d r o c o d o n e as a more effective analgesic than codeine with fewer reported side effects, but little data exist on which to base this claim. A l t h o u g h h y d r o c o d o n e has been shown to be a more effective analgesic than placebo,4, 5 only one study has directly compared the efficacy of a c o d e i n e / a c e t a m i n o p h e n combination with that of a hydrocodone/acetaminophen formulation. 6 This study found improved analgesia in the hydrocodone/acetaminophen group. However, part of the data was obtained retrospectively, and pain was not evaluated by a visual analog scale, which appears to be the most reliable method by which to measure pain. 7 F u r t h e r m o r e , t h e h y d r o c o d o n e / a c e t a m i n o p h e n group received a preparation containing 500 mg acetaminophen, which appears to be more effective than the 300-mg acetaminophen dose that was given in t h e c o d e i n e / a c e t a m i n o p h e n group. 8 No side effects were noted in the h y d r o c o d o n e / a c e t a m i n o p h e n group, and two patients in the codeine/acetaminophen group reported drowsiness. No further studies have compared the incidence of central nervous system side effects between these two agents. Early studies suggested that hydrocodone may be associated with fewer gastrointestinal side effects than codeine (particularly constipation), 9 but no recent studies h a v e addressed this question. The null hypotheses of this study were that hydrocodone and codeine are equianalgesic in combinations using equal amounts of acetaminophen and that side effects encountered using hydrocodone do not differ from those encountered with codeine when both are used in usual therapeutic doses.
MATERIALS A N D M E T H O D S Adult ED patients presenting with acute m u s c u l o s k e l e t a l pain to be treated on an outpatient basis were eligible for inclusion in the study. Patients with renal disease, hepatic disease, hypothyroidism, Addison's disease, urinary retention, known pregnancy, known psychiatric disease, or known or suspected drug abuse were excluded from this study. Patients 72/1101
using other analgesics were likewise excluded. Those with back pain also were excluded because of the multifactorial etiology and multidrug therapy often associated with this disorder. This study was approved by the University of Pittsburgh Institutional Review Board for Biomedical Research, and informed consent was obtained from each patient before enrollment. In a prospective, double-blind manner, eligible patients received a vial of 25 unlabeled tablets. With a computer-generated chart, patients were randomized to receive either 5 mg hydrocodone/500 mg acetaminophen or 30 mg codeine/500 mg acetaminophen. Study drugs were packaged into numbered vials by the pharmacy department at Presbyterian University Hospital according to the random number chart. Patients were instructed to take one dose at the onset of the study and every four hours thereafter as needed for pain. Pain intensity was evaluated at time zero and at one, two, four, eight, 24, and 48 hours by a visual analog scale (Figure). All patients were instructed in the proper use of the visual analog scale and completed the "time zero" form before discharge from the ED. Additional forms were completed by the patients at home at the appropriate intervals after taking the first dose. To minimize carryover bias, each form was placed in a sealed envelope immediately after completion. Follow-up calls were made at 24 and 48 hours by the principal investigator to ensure follow-up with completion of the pain scales and to elicit information about side effects. At the end of the 48-hour s t u d y period, p a t i e n t s were instructed to mail back the completed forms in a stamped, self-addressed envelope. The visual analog scale consisted of a 10-cm line, and conversion to a numerical score was determined by measuring from point 0 to the nearest 0.1 cm to give pain scores between 0.0 and 10.0. On each data form, patients were also asked to check off if they had experienced any side effects. Nausea, vomiting, constipation, drowsiness, dizziness, and "other side effects" were included on the form. During follow-up calls, all patients were asked if they had experienced any of these side effects. In addition, the patient's subjective evaluation of the Annals of Emergency Medicine
analgesic agent given was noted. Subjects who reported the analgesic as either inadequate or ineffective were considered treatment failures. Ordinal data were analyzed using Kruskal-Wallis analysis of variance, and n o m i n a l data were analyzed using Fisher's exact test. We estimated a decrease in pain scores of 25% or more as being clinically significant. The c~ error was set at .05; with 25 subjects per group, the study design had a m i n i m u m pretrial power of .8 to detect a 30% or greater difference between groups.
RESULTS Sixty-two patients were enrolled in this study over a 12-month period. Data on ll patients were unobtainable because of noncompliance with form completion, form return, or incorrect completion of pain scales. This occurred in seven hydrocodone/ acetaminophen and four codeine/acetaminophen patients (P = .27). In addition, one dropout occurred because of insufficient analgesia. This patient, who received codeine/acetaminophen, was not included in the data analysis. Median and mean pain scores are summarized (Table 1). Median pain scores at time zero were 6.80 in the hydrocodone/acetaminophen group versus 6.10 in the codeine/acetaminophen group (P > .5). Subsequent median pain scores, although lower in the h y d r o c o d o n e / a c e t a m i n o p h e n group at the later intervals of the study, did not differ significantly. Mean pain scores after time zero were consistently lower in the hydroc o d o n e / a c e t a m i n o p h e n group but also did not differ significantly. Side effects encountered in each group are summarized (Table 2), with some patients experiencing more than one. Eight hydrocodone/acetaminophen and 18 codeine/acetaminophen patients experienced one or more side effects (P = .005). Three h y d r o c o d o n e / a c e t a m i n o p h e n patients experienced either nausea or vomiting compared with six codeine/ acetaminophen patients (P = .23). Two patients in each group became c o n s t i p a t e d (P > .5). Six hydrocodone/acetaminophen patients reported central nervous system side effects ("drowsiness" or "dizziness") versus 16 codeine/acetaminophen patients (P < .005). The only "other" side effects reported related to either 20:10 October 1991
H Y D R O C O D O N E VS C O D E I N E Turturro et al
TABLE 1. Pain scores Time (hr) 0
1
2
4
8
24
48
5.99 6.10 2.15
4.63 4.60 2.21
4.35 3.90 2.21
4.40 4.60 1.85
3.89 4.10 2.16
3.59 3.60 2.63
2.65 2.00 2.42
Hydrocodone 6.03 Mean Median 6.80 SD 2.33
4.29 5.00 2.47
4.10 4.50 2.57
3.94 4.40 2.81
3.78 4.20 2.57
3.29 3.00 2.69
2.07 1.10 2.22
P
> .5
> .5
> .5
> .5
> .5
.16
Codeine Mean Median SD
> .5
TABLE 2. Side effects Central Nervous System or Gastrointestinal
Nausea or Vomiting
Constipation
Drowsy or Dizzy
18
6
2
16
8
3
2
6
.23
> .5
.0048*
Codeine Hydrocodone P
005*
*Stalistically significant.
FIGURE. Data collection sheet. Patient Name:
Time x hour
Vial #: No
Excruciating
Pain
Pain
Side Effects (please check): None _
Nausea Vomiting Constipation
_
Drowsiness
_ _
Dizziness
_ _
Other (please describe)
sedation or inadequate analgesia. No hydrocodone/acetaminophen p a t i e n t r e p o r t e d in e i t h e r follow-up telephone call or the side effect record that the analgesic was ineffective or inadequate compared w i t h six cod e i n e / a c e t a m i n o p h e n p a t i e n t s (P < .05). These patients were considered t r e a t m e n t failures.
DISCUSSION Although emergency physicians frequently treat patients in pain, inadequate and delayed analgesic ther20:10 October 1991
apy in the ED is c o m m o n , to Analgesia m u s t be i n d i v i d u a l i z e d for each p a t i e n t ' s c l i n i c a l p r e s e n t a t i o n for pain relief to be expeditions and safe. Our study involved the c o m m o n scenario of o u t p a t i e n t t r e a t m e n t of musculoskeletal pain; however, our findings m a y or m a y not extrapolate to the t r e a t m e n t of other painful conditions. Codeine has passed the test of t i m e as a relatively safe, m i l d oral narcotic analgesic. U n l i k e m o s t o t h e r narcotics, it r e t a i n s a p p r o x i m a t e l y two thirds of its parenteral potency w h e n given orally because of low first-pass m e t a b o l i s m . It produces little euphoria and therefore has a low abuse potential. However, both gastrointestinal and central nervous s y s t e m side effects are frequent w i t h its use. In addition, doses higher than the usual 30 to 60 m g produce little additional analgesia b u t d r a m a t i c a l l y increase the incidence of side effects, u H y d r o c o d o n e b i t a r t r a t e has l o n g been used as an analgesic and antit u s s i v e agent. Like codeine, it is a s c h e d u l e III a g e n t , a n d t h e r e f o r e fewer restrictions are involved in its p r e s c r i p t i o n t h a n are i n v o l v e d w i t h s c h e d u l e II a g e n t s s u c h as o x y codone. It m a y offer the advantage of having an u n f a m i l i a r n a m e to m a n y Annals of Emergency Medicine
patients, who m a y have preconceived n o t i o n s about codeine. W h y hydrocodone has not been used m o r e freq u e n t l y is u n k n o w n , a l t h o u g h this m a y be r e l a t e d to a l a c k of f a m i l i a r i t y w i t h t h i s drug. In a d d i t i o n , c o m m o n m i s p e r c e p t i o n s s u c h as a higher degree of sedation, euphoria, and addiction potential compared w i t h codeine m a y create fear of its use. N o n e of t h e s e m i s p e r c e p t i o n s has b e e n s u b s t a n t i a t e d in c l i n i c a l studies, b u t any of these u n t o w a r d effects m a y occur w i t h the use of any narcotic analgesic. M a n y clinicians rely p r i m a r i l y on nonsteroidal anti-inflammatory agents to treat m o s t acute pain syndromes. N o n s t e r o i d a l anti-inflammatory agents are effective analgesics w i t h no addiction potential, no sedative effects, and no tolerance. However, they have the potential to produce severe and life-threatening comp l i c a t i o n s . M a s s i v e and even fatal gastrointestinal hemorrhage m a y occur, renal insufficiency m a y be worsened, and a n a p h y l a x i s is seen occasionally. In contrast, the side effects associated with narcotic analgesic use are usually m i n o r and do not nec e s s i t a t e w i t h d r a w a l of t h e drug. E m e r g e n c y p h y s i c i a n s are often rel u c t a n t to use these agents for fear of inducing opioid addiction, but if care is used n o t to prescribe to p a t i e n t s w i t h k n o w n or s u s p e c t e d p s y c h o p a t h o l o g y or drug d e p e n d e n c e , t h e risk of inducing addiction is low. 1~,t3 In this study, lower p o s t - t r e a t m e n t pain scores were observed in the hydrocodone group. Because these scores did not reach statistical significance, we cannot refute previous research d e m o n s t r a t i n g greater or similar analgesia from hydrocodone compared w i t h codeine. A l t h o u g h efforts w e r e m a d e to e n s u r e c o m p l i a n c e , this was an o u t p a t i e n t study, and we could not ensure that pain scales were c o m p l e t e d at precisely the correct t i m e intervals. However, fewer t r e a t m e n t failures and side effects in the h y d r o c o d o n e group suggest t h a t hydrocodone m a y be a m o r e effective analgesic than codeine. We e n c o u n t e r e d a h i g h e r prevalence of side effects in both groups of patients than reported in previous research.4,5 These tended to be minor. However, because patients were specifically told w h i c h side effects could occur, they m a y have been m o r e conscious of t h e m than w o u l d otherwise 1102/73
HYDROCODONE VS CODEINE Turturro et al
have been expected. We found significantly fewer reports of sedation with hydrocodone. This may have clinical applicability to clinicians who need to use an analgesic for a patient in w h o m sedation is a concern. Nausea and vomiting, side effects that may limit the use of a given narcotic analgesic, occurred less frequently with hydrocodone. However, this was not statistically significant.
with significantly fewer side effects. Like codeine, it is a schedule III agent and m a y be a useful alternative in the outpatient treatment of mild-tomoderate pain. The authors are indebted to Mark S Aikman, RPh, and Central Pharmaceuticals, without whom this research would not have been possible. REFERENCES
CONCLUSION Hydrocodone bitartrate, when used for acute m u s c u l o s k e l e t a l pain in c o m b i n a t i o n w i t h acetaminophen, appears to provide at least equal, and in s o m e cases better, analgesia as similar preparations using codeine, as suggested by fewer treatment failures. Hydrocodone is also associated
74/1103
i. Paris PM, Weiss LD: Narcotic analgesics: The pure agonists, in Paris PM, Stewart RD (eds): Pain Management in Emergency Medicine. Norwalk, Connecticut, Appleton and Lange, 1988, p 125-153. 2. Kenner A: Erfrahrungen mit Dicodid. Munchen Med Wschr 1930;80:1718-1719. 3. Beaver WT: Combination analgesics. A m J Med 1984;77:38-53. 4. Beaver WT, McMillan D: Methodological considera~ tions in the evaluation of analgesic preparations: Acetaminophen (paracemetamol} and hydrocodone in post-
Annals of Emergency Medicine
partum pain. Br J Clin Pharmacol 1980;10:2i5S~223S. 5. Forbes JA, Bowser MW, Calderazzo JP, et ah An evaluation of the analgesic efficacy of three opioid-analgesic combinations in postoperative oral surgery pain. ] Oral Surg f981;39:108-112. 6. Hopkinson JH: Vicodin, a new analgesic: Clinical evaluation of efficacy and safety of repeated doses. Curr Ther Res 1978;24:633-645. 7. Huskisson EC, Scott J: Graphic representation of pain. Pain 1976;2:175-184. 8. Koch-Weser J: Drug t h e r a p y - A c e t a m i n o p h e n . N Bngl J Med 1976;295:1297-1300. 9. Stein P, Lowry P: Hycodan Dihydrocodeinone. A m Rev Tuberculosis i946;3:345-352. 10. Wilson JB, Pendleton JM: Oligoanalgesia in the . emergency department. A m J Emerg M e d 1989;7: 620-623. 11. Moertel CG: Relief of pain with oral medications. Aust N Z J Med 1976;6[suppl):l-8. I2. Porter J, Jick H: Addiction rare in patients treated with narcotics (letter). N Engl J Med 1980;302:123. 13. Taub A: Opioid analgesics in the treatment of intractable pain of non-neoplastic origin, in Kiahata L, Collins JG (eds}: Narcotic Analgesics in Anesthesiology Baitimore, Williams & Wilkins, 1982, p 199-208.
20:10 October 1991
Hydrocodone Versus Codeine in Acute Musculoskeletal Pain Study objectives: To evaluate the efficacy and prevalence of side effects of hydrocodone versus codeine in acute pain syndromes. Type of participants/setting: Sixty-two consecutive adult emergency department patients 18 to 70 years old with acute musculoskeletaI pain. Patients using other analgesics or having any contraindication to opioid therapy were excluded. In addition, 12 patients were excluded because of insufficient data or study dropout. Design/interventions: In a randomized, double-blind prospective manner, patients received either 5 mg hydrocodone with 500 mg acetaminophen or 30 mg codeine with 500 mg acetaminophen to take on discharge from the ED and every four hours thereafter as needed for pain. Measurements: Pain intensity was evaluated by a visual analog scale .at zero, one, two, four, eight, 24, and 48 hours. Specific side effects were sought, along with the number of patients reporting inadequate analgesia. Main results: Data were obtained on 50 subjects (25 per group). Mean and median pain scores did not differ significantly at time zero (x vs y, 6.03 vs 5.99 and 6.8 vs 6.1, respectively) or subsequent intervals. Side effects were noted in eight hydrocodone/acetaminophen and 18 codeine/acetaminophen patients (P = .005). No significant differences in gastrointestinal side effects were reported; however, less nausea or vomiting was reported in the hydrocodone group (P = .23). Central nervous system side effects (sedation or lightheadedness) were reported in six hydrocodone/ acetaminophen patients compared with 16 codeine/acetaminophen patients (P < .005). In addition, no hydrocodone/acetaminophen patients reported inadequate analgesia compared with six codeine/acetaminophen patients (P < .05). Conclusion: Although pain scores were not significantly different, hydrocodone may be a more effective analgesic than codeine in acute muscuIoskeletaI pain, as demonstrated by significantly fewer treatment failures. Central nervous system side effects are less common with hydrocodone than with codeine. [Turturro MA, Paris PM, Yealy DM, Menegazzi JJ: Hydrocodone versus codeine in acute musculoskeletai pain. Ann Emerg Med October 1991;20:1100-1103.]
INTRODUCTION Patients presenting to emergency departments often require acute pain management. Although several oral narcotic agents exist, little scientific data are available comparing their relative efficacies or the prevalence of side effects. Therefore, physicians choose agents largely on the basis of familiarity and drug company promotion. Codeine remains the most often prescribed oral narcotic analgesic.t Hydrocodone bitartrate, another schedule III agent, is a codeine congener that has been used since 1920 for its analgesic and antitussive properties. Early studies in the German literature suggested that 5 mg hydrocodone is equianalgesic to 30 mg codeine, z Because combining a narcotic analgesic with a non-narcotic analgesic such as aspirin or acetaminophen augments the analgesic potential, a drug companies have most often marketed these agents in combination preparations in which various amounts of acetaminophen are added to either codeine (Tylenol 3 ®) or hydrocodone (Anexsia ®, Co-Gesic ®, Vicodin ®, Zydone®). Codeine is usually prescribed in ei-
20:10 October 1991
Annals of Emergency Medicine
Michael A Turturro, MD*¢§ Paul M Paris, MD, FACEP¢¢ Donald M Yealy, MDt¢II James J Menegazzi, PhD$ Pittsburgh, Pennsylvania Temple, Texas From the University of Pittsburgh Affiliated Residency in Emergency Medicine;* Division of Emergency Medicine, University of Pittsburgh;¢ The Center for Emergency Medicine of Western Pennsylvania;¢ and The Mercy Hospital of Pittsburgh, Pittsburgh, Pennsylvania;§ and Division of Emergency Medicine, Texas A&M University College of Medicine, Temple, Texas.II Received for publication July 20, 1990. Revision received February 20, 1991. Accepted for publication March 21, 1991. Presented at the Scientific Assembly of the American College of Emergency Physicians in San Francisco, September 1990. Funding for this study was provided by The Center for Emergency Medicine of Western Pennsylvania and Central Pharmaceuticals. Address for reprints: Michael A Turturro, MD, Department of Emergency Medicine, The Mercy Hospital of Pittsburgh, 1400 Locust Street, Pittsburgh, Pennsylvania 15219.
1100/71
HYDROCODONE VS CODEINE Turturro et al
ther a 30-rag or 60-mg dose and hydrocodone in either a 5-rag or 7.5-rag dose. P h a r m a c e u t i c a l companies have also p r o m o t e d h y d r o c o d o n e as a more effective analgesic than codeine with fewer reported side effects, but little data exist on which to base this claim. A l t h o u g h h y d r o c o d o n e has been shown to be a more effective analgesic than placebo,4, 5 only one study has directly compared the efficacy of a c o d e i n e / a c e t a m i n o p h e n combination with that of a hydrocodone/acetaminophen formulation. 6 This study found improved analgesia in the hydrocodone/acetaminophen group. However, part of the data was obtained retrospectively, and pain was not evaluated by a visual analog scale, which appears to be the most reliable method by which to measure pain. 7 F u r t h e r m o r e , t h e h y d r o c o d o n e / a c e t a m i n o p h e n group received a preparation containing 500 mg acetaminophen, which appears to be more effective than the 300-mg acetaminophen dose that was given in t h e c o d e i n e / a c e t a m i n o p h e n group. 8 No side effects were noted in the h y d r o c o d o n e / a c e t a m i n o p h e n group, and two patients in the codeine/acetaminophen group reported drowsiness. No further studies have compared the incidence of central nervous system side effects between these two agents. Early studies suggested that hydrocodone may be associated with fewer gastrointestinal side effects than codeine (particularly constipation), 9 but no recent studies h a v e addressed this question. The null hypotheses of this study were that hydrocodone and codeine are equianalgesic in combinations using equal amounts of acetaminophen and that side effects encountered using hydrocodone do not differ from those encountered with codeine when both are used in usual therapeutic doses.
MATERIALS A N D M E T H O D S Adult ED patients presenting with acute m u s c u l o s k e l e t a l pain to be treated on an outpatient basis were eligible for inclusion in the study. Patients with renal disease, hepatic disease, hypothyroidism, Addison's disease, urinary retention, known pregnancy, known psychiatric disease, or known or suspected drug abuse were excluded from this study. Patients 72/1101
using other analgesics were likewise excluded. Those with back pain also were excluded because of the multifactorial etiology and multidrug therapy often associated with this disorder. This study was approved by the University of Pittsburgh Institutional Review Board for Biomedical Research, and informed consent was obtained from each patient before enrollment. In a prospective, double-blind manner, eligible patients received a vial of 25 unlabeled tablets. With a computer-generated chart, patients were randomized to receive either 5 mg hydrocodone/500 mg acetaminophen or 30 mg codeine/500 mg acetaminophen. Study drugs were packaged into numbered vials by the pharmacy department at Presbyterian University Hospital according to the random number chart. Patients were instructed to take one dose at the onset of the study and every four hours thereafter as needed for pain. Pain intensity was evaluated at time zero and at one, two, four, eight, 24, and 48 hours by a visual analog scale (Figure). All patients were instructed in the proper use of the visual analog scale and completed the "time zero" form before discharge from the ED. Additional forms were completed by the patients at home at the appropriate intervals after taking the first dose. To minimize carryover bias, each form was placed in a sealed envelope immediately after completion. Follow-up calls were made at 24 and 48 hours by the principal investigator to ensure follow-up with completion of the pain scales and to elicit information about side effects. At the end of the 48-hour s t u d y period, p a t i e n t s were instructed to mail back the completed forms in a stamped, self-addressed envelope. The visual analog scale consisted of a 10-cm line, and conversion to a numerical score was determined by measuring from point 0 to the nearest 0.1 cm to give pain scores between 0.0 and 10.0. On each data form, patients were also asked to check off if they had experienced any side effects. Nausea, vomiting, constipation, drowsiness, dizziness, and "other side effects" were included on the form. During follow-up calls, all patients were asked if they had experienced any of these side effects. In addition, the patient's subjective evaluation of the Annals of Emergency Medicine
analgesic agent given was noted. Subjects who reported the analgesic as either inadequate or ineffective were considered treatment failures. Ordinal data were analyzed using Kruskal-Wallis analysis of variance, and n o m i n a l data were analyzed using Fisher's exact test. We estimated a decrease in pain scores of 25% or more as being clinically significant. The c~ error was set at .05; with 25 subjects per group, the study design had a m i n i m u m pretrial power of .8 to detect a 30% or greater difference between groups.
RESULTS Sixty-two patients were enrolled in this study over a 12-month period. Data on ll patients were unobtainable because of noncompliance with form completion, form return, or incorrect completion of pain scales. This occurred in seven hydrocodone/ acetaminophen and four codeine/acetaminophen patients (P = .27). In addition, one dropout occurred because of insufficient analgesia. This patient, who received codeine/acetaminophen, was not included in the data analysis. Median and mean pain scores are summarized (Table 1). Median pain scores at time zero were 6.80 in the hydrocodone/acetaminophen group versus 6.10 in the codeine/acetaminophen group (P > .5). Subsequent median pain scores, although lower in the h y d r o c o d o n e / a c e t a m i n o p h e n group at the later intervals of the study, did not differ significantly. Mean pain scores after time zero were consistently lower in the hydroc o d o n e / a c e t a m i n o p h e n group but also did not differ significantly. Side effects encountered in each group are summarized (Table 2), with some patients experiencing more than one. Eight hydrocodone/acetaminophen and 18 codeine/acetaminophen patients experienced one or more side effects (P = .005). Three h y d r o c o d o n e / a c e t a m i n o p h e n patients experienced either nausea or vomiting compared with six codeine/ acetaminophen patients (P = .23). Two patients in each group became c o n s t i p a t e d (P > .5). Six hydrocodone/acetaminophen patients reported central nervous system side effects ("drowsiness" or "dizziness") versus 16 codeine/acetaminophen patients (P < .005). The only "other" side effects reported related to either 20:10 October 1991
H Y D R O C O D O N E VS C O D E I N E Turturro et al
TABLE 1. Pain scores Time (hr) 0
1
2
4
8
24
48
5.99 6.10 2.15
4.63 4.60 2.21
4.35 3.90 2.21
4.40 4.60 1.85
3.89 4.10 2.16
3.59 3.60 2.63
2.65 2.00 2.42
Hydrocodone 6.03 Mean Median 6.80 SD 2.33
4.29 5.00 2.47
4.10 4.50 2.57
3.94 4.40 2.81
3.78 4.20 2.57
3.29 3.00 2.69
2.07 1.10 2.22
P
> .5
> .5
> .5
> .5
> .5
.16
Codeine Mean Median SD
> .5
TABLE 2. Side effects Central Nervous System or Gastrointestinal
Nausea or Vomiting
Constipation
Drowsy or Dizzy
18
6
2
16
8
3
2
6
.23
> .5
.0048*
Codeine Hydrocodone P
005*
*Stalistically significant.
FIGURE. Data collection sheet. Patient Name:
Time x hour
Vial #: No
Excruciating
Pain
Pain
Side Effects (please check): None _
Nausea Vomiting Constipation
_
Drowsiness
_ _
Dizziness
_ _
Other (please describe)
sedation or inadequate analgesia. No hydrocodone/acetaminophen p a t i e n t r e p o r t e d in e i t h e r follow-up telephone call or the side effect record that the analgesic was ineffective or inadequate compared w i t h six cod e i n e / a c e t a m i n o p h e n p a t i e n t s (P < .05). These patients were considered t r e a t m e n t failures.
DISCUSSION Although emergency physicians frequently treat patients in pain, inadequate and delayed analgesic ther20:10 October 1991
apy in the ED is c o m m o n , to Analgesia m u s t be i n d i v i d u a l i z e d for each p a t i e n t ' s c l i n i c a l p r e s e n t a t i o n for pain relief to be expeditions and safe. Our study involved the c o m m o n scenario of o u t p a t i e n t t r e a t m e n t of musculoskeletal pain; however, our findings m a y or m a y not extrapolate to the t r e a t m e n t of other painful conditions. Codeine has passed the test of t i m e as a relatively safe, m i l d oral narcotic analgesic. U n l i k e m o s t o t h e r narcotics, it r e t a i n s a p p r o x i m a t e l y two thirds of its parenteral potency w h e n given orally because of low first-pass m e t a b o l i s m . It produces little euphoria and therefore has a low abuse potential. However, both gastrointestinal and central nervous s y s t e m side effects are frequent w i t h its use. In addition, doses higher than the usual 30 to 60 m g produce little additional analgesia b u t d r a m a t i c a l l y increase the incidence of side effects, u H y d r o c o d o n e b i t a r t r a t e has l o n g been used as an analgesic and antit u s s i v e agent. Like codeine, it is a s c h e d u l e III a g e n t , a n d t h e r e f o r e fewer restrictions are involved in its p r e s c r i p t i o n t h a n are i n v o l v e d w i t h s c h e d u l e II a g e n t s s u c h as o x y codone. It m a y offer the advantage of having an u n f a m i l i a r n a m e to m a n y Annals of Emergency Medicine
patients, who m a y have preconceived n o t i o n s about codeine. W h y hydrocodone has not been used m o r e freq u e n t l y is u n k n o w n , a l t h o u g h this m a y be r e l a t e d to a l a c k of f a m i l i a r i t y w i t h t h i s drug. In a d d i t i o n , c o m m o n m i s p e r c e p t i o n s s u c h as a higher degree of sedation, euphoria, and addiction potential compared w i t h codeine m a y create fear of its use. N o n e of t h e s e m i s p e r c e p t i o n s has b e e n s u b s t a n t i a t e d in c l i n i c a l studies, b u t any of these u n t o w a r d effects m a y occur w i t h the use of any narcotic analgesic. M a n y clinicians rely p r i m a r i l y on nonsteroidal anti-inflammatory agents to treat m o s t acute pain syndromes. N o n s t e r o i d a l anti-inflammatory agents are effective analgesics w i t h no addiction potential, no sedative effects, and no tolerance. However, they have the potential to produce severe and life-threatening comp l i c a t i o n s . M a s s i v e and even fatal gastrointestinal hemorrhage m a y occur, renal insufficiency m a y be worsened, and a n a p h y l a x i s is seen occasionally. In contrast, the side effects associated with narcotic analgesic use are usually m i n o r and do not nec e s s i t a t e w i t h d r a w a l of t h e drug. E m e r g e n c y p h y s i c i a n s are often rel u c t a n t to use these agents for fear of inducing opioid addiction, but if care is used n o t to prescribe to p a t i e n t s w i t h k n o w n or s u s p e c t e d p s y c h o p a t h o l o g y or drug d e p e n d e n c e , t h e risk of inducing addiction is low. 1~,t3 In this study, lower p o s t - t r e a t m e n t pain scores were observed in the hydrocodone group. Because these scores did not reach statistical significance, we cannot refute previous research d e m o n s t r a t i n g greater or similar analgesia from hydrocodone compared w i t h codeine. A l t h o u g h efforts w e r e m a d e to e n s u r e c o m p l i a n c e , this was an o u t p a t i e n t study, and we could not ensure that pain scales were c o m p l e t e d at precisely the correct t i m e intervals. However, fewer t r e a t m e n t failures and side effects in the h y d r o c o d o n e group suggest t h a t hydrocodone m a y be a m o r e effective analgesic than codeine. We e n c o u n t e r e d a h i g h e r prevalence of side effects in both groups of patients than reported in previous research.4,5 These tended to be minor. However, because patients were specifically told w h i c h side effects could occur, they m a y have been m o r e conscious of t h e m than w o u l d otherwise 1102/73
HYDROCODONE VS CODEINE Turturro et al
have been expected. We found significantly fewer reports of sedation with hydrocodone. This may have clinical applicability to clinicians who need to use an analgesic for a patient in w h o m sedation is a concern. Nausea and vomiting, side effects that may limit the use of a given narcotic analgesic, occurred less frequently with hydrocodone. However, this was not statistically significant.
with significantly fewer side effects. Like codeine, it is a schedule III agent and m a y be a useful alternative in the outpatient treatment of mild-tomoderate pain. The authors are indebted to Mark S Aikman, RPh, and Central Pharmaceuticals, without whom this research would not have been possible. REFERENCES
CONCLUSION Hydrocodone bitartrate, when used for acute m u s c u l o s k e l e t a l pain in c o m b i n a t i o n w i t h acetaminophen, appears to provide at least equal, and in s o m e cases better, analgesia as similar preparations using codeine, as suggested by fewer treatment failures. Hydrocodone is also associated
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Annals of Emergency Medicine
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