Combination hydrocodone and ibuprofen versus combination codeine and acetaminophen for the treatment of chronic pain

doi:10.1016/S0149-2918(00)80060-0

Clinical Therapeutics

Volume 22, Issue 7, July 2000, Pages 879-892

https://doi.org/10.1016/S0149-2918(00)80060-0 Get rights and content

Abstract

Objective

The objective of this study was to compare the effectiveness of combination hydrocodone 7.5 mg and ibuprofen 200 mg with that of combination codeine 30 mg and acetaminophen 300 mg for the treatment of chronic pain.

Background

Hydrocodone 7.5 mg with ibuprofen 200 mg is the only approved fixed-dose combination analgesic containing an opioid and ibuprofen.

Methods

In this randomized, parallel-group, double-blind, repeated-dose, active-comparator, 4-week, multicenter study, 469 patients were randomly assigned to receive a 1-tablet (n = 156) or 2-tablet (n = 153) dose of combination hydrocodone 7.5 mg and ibuprofen 200 mg (HI1 and HI2, respectively) or a 2-tablet dose of combination codeine 30 mg and acetaminophen 300 mg (CA, n = 160), the active comparator, every 6 to 8 hours as needed for pain. Efficacy was measured through pain relief scores, number of daily doses of study medication, number of daily doses of supplemental analgesics, number of patients who discontinued therapy due to an unsatisfactory analgesic response, and global assessment scores.

Results

Of the 469 patients, 255 (54.4%) were female and 214 (45.6%) were male. The mean age was 51.1 years. Types of chronic pain included back (214; 45.6%), arthritic (145; 30.9%), other musculoskeletal (65; 13.9%), cancer (6; 1.3%), diabetic neuropathic (3; 0.6%), postherpetic neuralgic (5; 1.1%), other neurologic (21; 4.5%), and other unclassified chronic pain (10; 2.1%). During the 48 hours prior to the study, 351 (74.8%) patients had been treated with opioid or opioid-nonopioid combination analgesics. The overall mean daily pain relief score was significantly greater in the HI2 group (2.25 ± 0.89) than in the HI1 group (1.98 ± 0.87) (P = 0.003) or the CA group (1.85 ± 0.96) (P < 0.001). The overall mean number of daily doses of study medication was significantly less in the HI2 group (2.94 ± 0.99) than in the HI1 group (3.23 ± 0.76) (P = 0.036) or the CA group (3.26 ± 0.75) (P = 0.014). The overall mean number of daily doses of supplemental analgesics was significantly less in the HI2 group (0.24 ± 0.49) than in the HI1 group (0.34 ± 0.58) (P = 0.021) or CA group (0.49 ± 0.85) (P = 0.010). The number of patients who discontinued treatment due to an unsatisfactory analgesic response was significantly less in the HI2 group (2; 1.3%) than in the CA group (12; 7.5%) (P = 0.008). HI2 was more effective than HI1 and CA as measured by pain relief scores for week 1 (P < 0.001 vs HI1 and CA), week 2 (P < 0.001 vs HI1 and CA), and week 3 (P = 0.008 vs HI1 and P < 0.001 vs CA); daily doses of study medication for week 1 (P = 0.019 vs HI1 and P = 0.011 vs CA); daily doses of supplemental analgesics for week 1 (P = 0.010 vs HI1 and CA); and global assessment scores for week 1 (P = 0.018 vs HI1 and (P < 0.001 vs CA), week 2 (P = 0.005 vs HI1 and (P < 0.001 vs CA), and week 4 (P = 0.013 vs HI1 and (P = 0.023 vs CA). There were no significant differences between HI1 and CA in any efficacy variable. There were no significant differences in the number of patients experiencing adverse events in the HI2 (127; 83%), HI1 (124; 79.5%), and CA (129; 80.6%) groups. However, the mean number of patients who discontinued treatment due to adverse events was significantly greater in the HI2 group (40; 26.1%) than in the HI1 group (23; 14.7%) ((P = 0.013).

Conclusions

The results of this study suggest that 2-tablet doses of combination hydrocodone 7.5 mg and ibuprofen 200 mg may be more effective than either 1-tablet doses of this combination or 2-tablet doses of combination codeine 30 mg and acetaminophen 300 mg. Moreover, 1-tablet doses of combination hydrocodone 7.5 mg and ibuprofen 200 mg may be as effective as 2-tablet doses of combination codeine 30 mg and acetaminophen 300 mg.

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Citation Excerpt :
Given recent warnings on codeine and tramadol, hydrocodone is becoming the more popular choice in treating moderate-severe pain in the pediatric population [22,23]. This is also apparent in the adult population with comparisons between hydrocodone and codeine demonstrating greater efficacy of pain control among hydrocodone groups [24,25]. While these studies cannot be directly applied to our patient population, they do show that hydrocodone is a viable alternative.
This prospective study aimed to survey pediatric patients and their parents after tonsillectomy to assess their pain management utilization and satisfaction.
Tonsillectomy is the second most common surgical procedure performed in pediatric patients. Postoperative recovery is often associated with high levels of pain and severe functional limitations. There is currently no consensus on pain control regimens. Additionally, a recent FDA Black Box Warning on narcotic use has caused more uncertainty in appropriate pain control regimens.
111 pediatric patients (≤18 years) included in this study underwent tonsillectomy with or without adenoidectomy between October 2013 and August 2015. Postoperatively, each patient/parent was counseled to alternate on an over-the-counter regimen of acetaminophen and ibuprofen and given an additional as-needed acetaminophen with hydrocodone prescription. A survey was administered during the patient's 2-week follow-up that included questions regarding pain levels, worst post-op pain day, pain medications taken during recovery, and patient/parental perceived satisfaction of having the acetaminophen with hydrocodone prescription.
84 patients/parents (75.7%) felt that OTC medications were not adequate for pain control and used hydrocodone at least once. Between those who took hydrocodone versus those who did not, there was no significant difference in mean age (6.7 ± 2.9 vs. 6.0 ± 2.4 years), percentage of patients with severe pain (36.9% vs. 22.2%) and worst post-op pain day (4.3 ± 1.5 vs. 3.9 ± 1.9 days) (p > 0.05). However, regardless of pain control regimen followed, the majority of patients/parents found it valuable to have the hydrocodone prescription (p = 0.004).
Post-tonsillectomy patients and their parents find being provided with an acetaminophen-hydrocodone prescription is therapeutically valuable, and many find it necessary in their postoperative pain management. However, further studies are needed to determine patient factors that influence narcotic utilization.
Comparison of Unintentional Exposures to Codeine and Hydrocodone Reported to Texas Poison Centers
2016, Journal of Emergency Medicine
Hydrocodone has recently been reclassified as a Schedule II drug by the United States Drug Enforcement Administration and Food and Drug Administration in order to curtail prescription drug abuse. There is concern that analgesic substitutes, such as codeine, will not be as safe or effective.
The purpose of this study is to compare the demographics, adverse events, and medical outcomes of patients who had unintentional hydrocodone or codeine exposures through the use of a state's poison center database.
The Texas Poison Center Network's database was utilized to find all reported unintentional ingestions or adverse reactions of products containing codeine or hydrocodone. Comparisons were made between the two medications by calculating the rate ratios (RR) and 95% confidence intervals (CI).
Children aged 5 years or younger were more exposed to codeine (51.6%). Hydrocodone exposures had more serious outcomes (11% vs. 9%; RR = 0.82; 95% CI 0.73–0.91) and had more nausea (7.1% vs. 2.8%; RR = 0.4; 95% CI 0.32–0.48) and vomiting (6.5% vs. 3.3%; RR = 0.51; 95% CI 0.43–0.62). Hydrocodone had a higher rate of intravenous fluids administration (2.4% vs. 1.7%; RR = 0.71; 95% CI 0.54–0.92) and antiemetics (0.4% vs. 0.1%; RR = 0.23; 95% CI 0.08–0.64). Codeine was more closely associated with dermal reactions and patients were given antihistamines (2.5% vs. 1.3%; RR = 1.88; 95% CI 1.46–2.41) more frequently. Cardiovascular side effects, ataxia, and headache occurred equally between the groups.
Both drugs had a wide array of reported side effects, but the overall incidence of serious outcomes was low.
Evaluation and comparison of postmortem hydrocodone concentrations in peripheral blood, central blood and liver specimens: A minimal potential for redistribution
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Postmortem changes can alter the concentration of drugs in the vascular compartment as compared with concentrations originally present at the time of death. Numerous drugs have been reported to increase due to postmortem redistribution (PMR). The potential for PMR of hydrocodone, a therapeutic opioid analgesic used to manage pain, is of particular interest due to its wide use. Hydrocodone concentrations in 39 peripheral blood, central blood, and liver specimens were compared. Dihydrocodeine (DHC), a commonly encountered hydrocodone metabolite, was present in 61% of the cases with an average concentration that was 29% of the hydrocodone value. Central blood to peripheral blood hydrocodone ratios were well correlated (R² = 0.965) with an average (±S.D.) of 1.3 (±0.35) and a median of 1.2. The liver to peripheral blood (L/P) hydrocodone ratio was also well correlated (R² = 0.915) with an average (±S.D.) of 3.4 (±1.7) L/kg and a median of 3.0 L/kg. This low L/P ratio suggests that hydrocodone is unlikely to undergo substantial PMR changes.
Minor and Short-Acting Analgesics, Including Opioid Combination Products
2013, Practical Management of Pain: Fifth Edition
Minor and short-acting analgesics, including opioid combination products
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Acetaminophen ototoxicity after acetaminophen/hydrocodone abuse: Evidence from two parallel in vitro mouse models
2010, Otolaryngology - Head and Neck Surgery
Citation Excerpt :
Many studies have looked at the safety and efficacy of acetaminophen in combination with hydrocodone or codeine, including two prospective randomized controlled studies.12,13 The largest, most long-term of these studies is a multicenter trial comparing the efficacy of acetaminophen/codeine versus acetaminophen/hydrocodone in 469 patients treated for a myriad of chronic pain syndromes.12 Patients received no more than eight pills per day and were followed for one month.
Acetaminophen/hydrocodone, a commonly used analgesic preparation, has been linked to rapidly progressing sensorineural hearing loss in human patients. The cellular and molecular mechanisms underlying the ototoxic effects of this drug combination are currently unknown, but are usually associated with high doses of hydrocodone. This study was aimed at identifying the specific agent responsible for hearing loss from toxic killing of cochlear sensory cells.
Dose-response study.
University laboratory and private research facility.
Math1 green fluorescent protein neonatal mouse cochlear cultures as well as a mouse auditory cell line (HEI-OC1) were exposed in vitro to different concentrations of acetaminophen, hydromorphone (the active metabolite of hydrocodone), and the micronutrient L-carnitine, either alone or combined. Using fluorescent and light microscopy, we quantified the sensory hair cells from a 600-μm basal segment before and after treatment. Acetaminophen/hydrocodone-induced apoptosis of HEI-OC1 was evaluated by caspase 3-activation studies. Statistically significant cell survival was determined with Student t test and analysis of variance.
Cell death was associated mainly with exposure to acetaminophen, was slightly potentiated when combined with hydromorphone, and was partially prevented by L-carnitine. Exposure to hydrocodone or hydromorphone alone failed to kill either cochlear hair cells or HEI-OC1 cells.
Our findings point to acetaminophen, rather than hydrocodone, as the primary cytotoxic agent. Hydrocodone, however, may work synergistically with acetaminophen, increasing the damage to auditory cells. These findings are an important first step toward understanding the mechanism of acetaminophen/hydrocodone ototoxicity and may lead to future treatment strategies for hearing loss from ototoxic medications.

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View full text

Combination hydrocodone and ibuprofen versus combination codeine and acetaminophen for the treatment of chronic pain

Abstract

Objective

Background

Methods

Results

Conclusions

Am J Med.

Am J Med.

J Am Dent Assoc.

Am J Med.

Am J Med.

Oral Surg Oral Med Oral Pathol.

Eur J Pharmacol.

Hepatology

Lancet

Lancet

Lancet

Nonsteroidal anti-inflammatory analgesics and their combinations with opioids

Acute Pain Management: Operative or Medical Procedures and Trauma

Clinical Practice Guideline No. 9

Synthetic substances with morphine-like-effect—Clinical experience: potency, side-effects, addiction liability. 5. Hydrocodone (dihydrocodeinone)

Bull WHO.

Analgesic efficacy of a combination of hydrocodone with ibuprofen in postoperative pain

Clin Pharmacol Ther.