The effects of morphine on human articular cartilage of the knee: An in vitro study

doi:10.1053/jars.2002.32587

Arthroscopy: The Journal of Arthroscopic & Related Surgery

Volume 18, Issue 6, July 2002, Pages 631-636

https://doi.org/10.1053/jars.2002.32587 Get rights and content

Abstract

Purpose: The purpose of this study was to determine the metabolic, histologic, and ultrastructural effects of morphine and its combination with saline and bupivacaine on human articular cartilage. Type of Study: In vitro study. Methods: Nonfibrillated human articular cartilage was harvested and transferred into an experimental culture consisting of a control medium, saline, or a combination of morphine/saline or morphine/saline/bupivacaine for 12, 24, or 72 hours. Each sample was radiolabeled to assess proteoglycan synthesis. Histologic and ultrastructural effects were also examined. Results: We found a significant, dose-related, transient decrease in ³⁵SO₄ incorporation in the morphine/saline samples at 12 hours, and in the saline only samples at 24 hours. We found no evidence of histologic or ultrastructural damage to the cartilage. Conclusions: Morphine and saline can both produce a transient decrease in ³⁵SO₄ incorporation that normalizes by 72 hours. This study does not suggest any contraindication to the use of intra-articular morphine as a postoperative analgesic.

Arthroscopy: The Journal of Arthroscopic and Related Surgery, Vol 18, No 6 (July-August), 2002: pp 631–636

Section snippets

Methods

Necessary materials purchased for the study included (1) Dulbecco’s Modified Eagle Medium (DMEM)/Ham’s F-12 Medium in 1:1 ratio, fetal bovine serum, human transferrin, L-glutamine, L-ascorbate, mycostatin, penicillin, and streptomycin (Signa Chemical, St. Louis, MO); (2) Sulfur-35 radionuclide (10 mCi/mL ³⁵SO₄) (DuPont NEN Research Products, Boston, MA); and (3) Aquasol-2 scintillation cocktail (Packard Instruments, Meriden, CT).

Human articular cartilage was harvested at the time of total knee

Results

The average sulfate incorporation values for the control explants (media only) were 7,457 ± 1,178 DPM/mg at 12 hours; 6,919 ± 678 DPM/mg at 24 hours; and 5,765 ± 417 DPM/mg at 72 hours. The average values for the saline only explants were 5,764 ± 1,298 DPM/mg at 12 hours; 4,308 ± 614 DPM/mg at 24 hours; and 4,792 ± 692 DPM/mg at 72 hours. For the explants tested in 0.04 mg/mL morphine sulfate, the average values were 5,490 ± 574 DPM/mg at 12 hours; 5,485 ± 177 DPM/mg at 24 hours; and 5,680 ±

Discussion

Contrary to the effect of morphine on articular cartilage, the effects of saline and bupivacaine on articular cartilage have been studied. In 1985, Nole et al.⁸ reported that saline solution mixed with bupivacaine had a profound effect on articular cartilage, causing acute inhibition of ³⁵SO₄ incorporation into intact animal articular cartilage slices in vitro. Bupivacaine also appeared to cause a slight additive inhibition. However, the ability to incorporate ³⁵SO₄ into proteoglycan is

Acknowledgements

Acknowledgment: The authors express their appreciation to John A. Gross, M.D., for reviewing the manuscript and helping with the graph designs.

References (10)

C Stein et al.
Antinociceptive effects of mu and kappa agonists in inflammation are enhanced by a peripheral opioid receptor-specific mechanism
Eur J Pharmacol
(1988)
J Dalsgaard et al.
Low dose intra-articular morphine analgesia in day case knee arthroscopy: A randomized, double-blinded, prospective study
Pain
(1994)
R Nole et al.
Bupivacaine and saline effects on articular cartilage
Arthroscopy
(1985)
C Stein et al.
Analgesic effect of intra-articular morphine after arthroscopic knee surgery
N Engl J Med
(1991)
GP Joshi et al.
Intra-articular morphine for pain relief after knee arthroscopy
J Bone Joint Surg Br
(1992)

There are more references available in the full text version of this article.

Cited by (27)

Dexamethasone Does not Compensate for Local Anesthetic Cytotoxic Effects on Tenocytes: Morphine or Morphine Plus Dexamethasone May Be a Safe Alternative
2022, Arthroscopy, Sports Medicine, and Rehabilitation
The purposes of this in vitro study were to investigate whether the addition of dexamethasone can compensate for any cytotoxic effects of the amide-type local anesthetics (LA) bupivacaine and ropivacaine and whether morphine and morphine-6-glucuronide (M6G) may be a safe alternative for peritendinous application.
Biopsies of human biceps tendons (n = 6) were dissected and cultivated. Cells were characterized by the expression for tenocyte markers, collagen I, biglycan, tenascin C, scleraxis, and RUNX via reverse transcriptase-polymerase chain reaction and immunohistochemistry. Tenocytes were incubated with bupivacaine, ropivacaine, morphine, M6G, or a saline control with and without addition of dexamethasone for 15, 60, or 240 min. Cell viability was determined by quantifying the presence of adenosine-triphosphate.
Significant time-dependent cytotoxic effects were observed for LA after all exposure times. After 15, 60, and 240 minutes, cell viability decreased to 81.1%, 49.4% and 0% (P < .001) for bupivacaine and to 81.4%, 69.6%, and 9.3% (P < .001) for ropivacaine compared to saline control. Dexamethasone did not compensate for these cytotoxic effects. Cell viability was not affected after 15, 60-min exposures to morphine and M6G but decreased significantly (P < .001) after 240 minutes compared to saline control. However, in combination with dexamethasone, tenocyte viability was significantly increased at all times for morphine (P < .01) and at 15 and 60 minutes for M6G (P < .01).
The results showed that amide-type LA have a time-dependent cytotoxic effect on human tenocytes in vitro, which could not be compensated for by dexamethasone, whereas morphine and M6G had no cytotoxic effects on tenocytes after 15 and 60 minutes. The addition of dexamethasone to morphine and M6G had a positive effect on viability, which increased significantly compared to the opioids.
It is known that amide-type local anesthetics used for local joint analgesia have chondrotoxic side-effects. The combined application of morphine and dexamethasone may be a safe alternative.
Single-dose intra-articular morphine after arthroscopic knee surgery: A meta-analysis of randomized placebo-controlled studies
2013, Arthroscopy - Journal of Arthroscopic and Related Surgery
The purpose of this quantitative meta-analysis is to appraise the efficacy and side effects of intra-articular morphine in patients undergoing arthroscopic knee surgery.
The comprehensive literature search, using Medline (1966 to 2013), the Cochrane Central Register of Controlled Trials, and EMBASE databases, was conducted to identify randomized placebo-controlled trials that used single-dose intra-articular morphine for postoperative pain. The relative risk (RR), standardized mean difference (SMD), and their corresponding 95% confidence intervals (CIs) were calculated using statistical software.
Twenty-six articles were included in the meta-analysis. The acute postoperative visual analog scale (VAS) pain scores of the morphine group compared with the control group were significantly lower (SMD, −1.16; 95% CI, −1.79 to −0.53; P = .0003). The number of patients requiring supplementary analgesia was also significantly reduced (RR, 0.80; 95% CI, 0.70 to 0.93; P = .008), and there was a significant difference in the time to first analgesic request (SMD, 1.47; 95% CI, 0.49 to 2.44; P = .003) when the morphine group was compared with the placebo group. However, there was no significant difference in side effects between the morphine group and the control group (RR, 0.93; 95% CI, 0.67 to 1.28; P = .65).
The key findings of the present study were that the administration of single-dose intra-articular morphine at the end of arthroscopic knee surgery provided better pain relief, reduced the need for supplementary analgesics, and lengthened the time interval before the first request for additional analgesic medication, all with short-term side effects similar to those of the saline placebo.
Level II, meta-analysis of Level I-II studies.
Targeting inflammation and wound healing by opioids
2013, Trends in Pharmacological Sciences
Citation Excerpt :
In this model i.a. morphine was found to diminish joint swelling, inflammatory cells, protein, amyloid A, prostaglandin, and bradykinin in synovial fluid [48–50]. Importantly, no tissue damage was attributable to i.a. morphine [51,52]. Taken together, the majority of studies showed consistent μ-opioid-receptor-mediated reduction of peripheral inflammation, whereas possible adverse effects of κ-ligands need to be taken into consideration [25].
Opioid receptors are expressed on peripheral sensory nerve endings, cutaneous cells, and immune cells; and local application of opioids is used for the treatment of inflammatory pain in arthritis, burns, skin grafts, and chronic wounds. However, peripherally active opioids can also directly modulate the inflammatory process and wound healing. Here, we discuss the underlying mechanisms of opioid action and the conceivable therapeutic approaches for opioid treatment, as investigated in experimental and clinical studies. A large number of in vitro experiments and animal model investigations have produced evidence that peripherally active opioids can reduce plasma extravasation, vasodilation, proinflammatory neuropeptides, immune mediators, and tissue destruction. In contrast to currently available anti-inflammatory agents, opioids have not demonstrated organ toxicity, thus making them interesting candidates for drug development. Few clinical studies have tapped into this potential to date.
Analgesic efficacy of intra-articular morphine in experimentally induced radiocarpal synovitis in horses
2010, Veterinary Anaesthesia and Analgesia
Citation Excerpt :
In an in vitro study, proteoglycan synthesis of human articular cartilage was only mildly altered by morphine. These alterations, which were similar to those seen after in vitro saline treatment, were reversed after 72 hours and hence the study concluded that the results did ‘not suggest any contraindication to the use of intra-articular morphine as a post-operative analgesic’ (Jaureguito et al. 2002). The decision to study the analgesic effect of IA morphine in experimentally induced lameness was based on observation from studies in humans where it has been clearly shown that at least moderate pain is a prerequisite for detecting a difference between different analgesics (Kalso et al. 2002).
To compare the analgesic effect of intra-articular (IA) and intravenous (IV) morphine in horses with experimentally induced synovitis.
Eight adult horses.
Randomized, observer blinded, double dummy trial with sequential crossover design.
Radiocarpal synovitis was induced by IA injection of lipopolysaccharide on two occasions separated by a 3-week washout period. In one study period horses received treatment IA; morphine IA (0.05 mg kg⁻¹) plus saline IV and in the other study period they received treatment IV; saline IA plus morphine IV (0.05 mg kg⁻¹). Lameness and pain were evaluated repeatedly by two observers throughout each of the two 168-hour study periods. Pain was evaluated by use of a visual analogue scale of pain intensity (VAS) and a composite measure pain scale (CMPS). Comparison of treatments was performed by analysis of variance with repeated measurements. Significance level was set to p ≤ 0.05. Inter-observer agreement and agreement between the VAS and CMPS was assessed by use of the Bland–Altman method.
Intra-articular injection of LPS elicited a marked synovitis resulting in lameness and pain. IA morphine resulted in significantly less lameness than IV morphine (p = 0.03). CMPS (p = 0.09) and VAS (p = 0.10) pain scores did not differ significantly between treatments. Inter-observer agreement of the CMPS was classified as good, but only fair for the VAS. Agreement between the two pain scales was considered fair.
An analgesic effect of IA morphine was demonstrated by significantly reduced lameness scores. The results support the common practice of including IA morphine in a multimodal analgesic protocol after arthroscopic surgery, although further studies in clinical cases are needed. The employed CMPS had good reproducibility, and was easy to use, but may have limited sensitivity at mild intensity pain.
Analgesic efficacy of the intra-articular administration of high doses of morphine in patients undergoing total knee arthroplasty
2010, Revista Brasileira de Anestesiologia
Although the efficacy of intra-articular (IA) morphine is still controversial, it has been shown that higher doses promote better results and consequently decrease postoperative analgesic consumption, characterizing a dose-dependent peripheral action. A controlled, randomized, double-blind study was undertaken to evaluate the efficacy of the intra-articular administration of 10 mg of morphine in patients undergoing total knee arthroplasty.
Fifty patients undergoing total knee arthroplasty were randomly divided into two groups: the treatment group received 10 mg (1 mL) of intra-articular morphine diluted in 19 mL of NS, while the control group received the intra-articular administration of 20 mL of NS, both after closure of the capsule at the end of the surgery. On demand subcutaneous morphine was available for residual pain. The following parameters were evaluated: pain severity according to the numeric scale (NS), 2 h (M1), 6 h (M2), 12 h (M3), and 24 h (M4) after the IA injection; time until the first request of analgesic; analgesic consumption, and side effects.
The treatment group had lower NS than the control group in M1 and M2, while significant differences were not observed in the other moments. The time until the first request of analgesics was significantly higher in the treatment group, and analgesic consumption in the first 24 hours was also lower in this group. The incidence of side effects did not differ between both groups. We concluded that the postoperative IA administration of 10 mg of morphine promoted a longer period without rescue analgesics and reduced their consumption in the first 24 hours.
Apesar da eficácia da morfina intra-articular (IA) permanecer controversa, tem-se mostrado que doses maiores promovem melhores resultados e, consequentemente, menor consumo pós-operatório de analgésico, caracterizando, assim, efeito dose-dependente na ação periférica. Foi conduzido estudo controlado, aleatório e duplamente encoberto para avaliar a eficácia de 10 mg de morfina por via intra-articular em pacientes submetidos à artroplastia total de joelho.
Foram avaliados 50 pacientes submetidos à artroplastia total de joelho, distribuídos aleatoriamente em dois grupos: o grupo-tratamento recebeu 10 mg (1 mL) de morfina por via intra-articular diluído em 19 mL de solução fisiológica a 0,9% (SF), enquanto o grupo-controle recebeu injeção intra-articular contendo 20 mL de SF, ambos após o fechamento da cápsula articular, ao final da operação. Morfina subcutânea sob demanda esteve disponível para dor residual. As seguintes variáveis foram avaliadas: intensidade da dor graduada na Escala Numérica (EN) às 2 h (M1), 6 h (M2), 12 h (M3) e 24 h (M4) após injeção IA; tempo para primeira solicitação de analgésico; consumo de analgésicos e efeitos adversos.
O grupo-tratamento apresentou menores valores na EN que o grupo-controle em M1 e M2, enquanto que nos outros momentos não houve diferença significativa. O intervalo para primeira solicitação de analgésicos foi significativamente maior no grupo-tratamento e o consumo de analgésicos nas primeiras 24 horas foi menor neste grupo. Não houve diferença entre incidência de efeitos adversos entre os grupos. Concluiu-se que 10 mg de morfina reduziram dor pós-operatória 2 e 6 horas após injeção IA, promoveram maior período sem analgésico de resgate e reduziram seu consumo nas primeiras 24 horas.
A pesar de que la eficacia de la morfina intra-articular (IA), permanece como algo controvertido, ha quedado demostrado que las dosis mayores generan mejores resultados y consecuentemente, un menor consumo postoperatorio de analgésico, caracterizando así, el efecto dosis-dependiente en la acción periférica. Fue realizado un estudio controlado, aleatorio y doble ciego para evaluar la eficacia de 10 mg de morfina por vía intra-articular en pacientes sometidos a la artroplastia total de rodilla.
Se evaluaron 50 pacientes sometidos a la artroplastia total de rodilla, distribuidos aleatoriamente en dos grupos: el grupo tratamiento recibió 10 mg (1 mL) de morfina por vía intra-articular diluido en 19 mL de solución fisiológica al 0,9% (SF), mientras que el grupo control recibió una inyección intra-articular con 20 mL de SF, ambos después del cierre de la cápsula articular, al final de la operación. La morfina subcutánea bajo demanda, estuvo disponible para el dolor residual. Se evaluaron las siguientes variables: intensidad del dolor graduada en la Escala Numérica (EN) a las 2h (M1), 6h (M2), 12h (M3) y 24h (M4), después de la inyección IA; tiempo para la primera solicitación de analgésico; y consumo de analgésicos y efectos adversos.
El grupo tratamiento presentó menores valores en la EN que el grupo control en M1 y M2, mientras que en los otros momentos, no se registró ninguna diferencia significativa. El intervalo para la primera solicitación de analgésicos fue significantemente mayor en el grupo tratamiento y el consumo de analgésicos en las primeras 24 horas fue menor en ese grupo. No hubo diferencia entre la incidencia de efectos adversos entre los grupos. Llegamos a la conclusión, de que 10 mg de morfina redujeron el dolor del postoperatorio entre 2 y 6 horas después de aplicada la inyección IA, y se generó un periodo mayor sin analgésico de rescate reduciendo su consumo en las primeras 24 horas.
In Vitro Exposure to 0.5% Bupivacaine Is Cytotoxic to Bovine Articular Chondrocytes
2006, Arthroscopy - Journal of Arthroscopic and Related Surgery
Purpose: Intra-articular use of 0.5% bupivacaine is common in arthroscopic surgery. This study was conducted to test the hypotheses that (1) 0.5% bupivacaine is toxic to articular chondrocytes, and (2) the intact articular surface protects chondrocytes from the effects of short-term exposure to 0.5% bupivacaine. Methods Freshly isolated bovine articular chondrocytes were prepared into alginate bead cultures and were treated with 0.5% bupivacaine solution or 0.9% saline for 15, 30 or 60 minutes, washed, and returned to growth media. Chondrocytes were recovered from alginate 1 hour, 1 day, and 1 week after bupivacaine exposure; they were fluorescently labeled to identify apoptotic and dead cells and were analyzed by flow cytometry. Twelve osteochondral cores were harvested from bovine knees. The superficial 1 mm of cartilage was removed from 6 cores (top-off). Intact and top-off cores were submerged in 0.9% saline or 0.5% bupivacaine solution for 30 minutes and then maintained in chondrocyte growth media for 24 hours. Live-cell/dead-cell fluorescent imaging was assessed using confocal microscopy. Results: Greater than 99% chondrocyte death/apoptosis was observed in all bupivacaine-exposed alginate bead cultures compared with 20% cell death in saline-treated controls (P < .05). Osteochondral cores with intact surfaces treated with 0.5% bupivacaine showed 42% dead chondrocytes. When the articular surface was removed, 0.5% bupivacaine resulted in increased cell death, with 75% dead chondrocytes (P < .05). Conclusions: Results show that 0.5% bupivacaine solution is cytotoxic to bovine articular chondrocytes and articular cartilage in vitro after only 15 to 30 minutes’ exposure. The intact bovine articular surface has some chondroprotective effects. Clinical Relevance: Because healthy chondrocytes are important for maintenance of the cartilage matrix, chondrocyte loss may contribute to cartilage degeneration. This study shows a cytotoxic effect of 0.5% bupivacaine solution on bovine articular chondrocytes in vitro. Although these results cannot be directly extrapolated to the clinical setting, the data suggest that caution should be exercised in the intra-articular use of 0.5% bupivacaine.

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^*: Supported by the University of Chicago Section of Orthopaedic Surgery and Rehabilitation Medicine.

^**: All work was performed in the Section of Orthopaedic Surgery and Rehabilitation Medicine at the University of Chicago, Chicago, IL.

^★: Address correspondence and reprint requests to Joseph F. Wilcox, M.D., Northeast Orthopedics, 164 Wetherby Lane, Westerville, OH 43081, U.S.A. E-mail: [email protected]

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Arthroscopy: The Journal of Arthroscopic & Related Surgery

Abstract

Section snippets

Methods

Results

Discussion

Acknowledgements

References (10)

Antinociceptive effects of mu and kappa agonists in inflammation are enhanced by a peripheral opioid receptor-specific mechanism

Eur J Pharmacol

Low dose intra-articular morphine analgesia in day case knee arthroscopy: A randomized, double-blinded, prospective study

Pain

Bupivacaine and saline effects on articular cartilage

Arthroscopy

Analgesic effect of intra-articular morphine after arthroscopic knee surgery

N Engl J Med

Intra-articular morphine for pain relief after knee arthroscopy

J Bone Joint Surg Br

Cited by (27)

Dexamethasone Does not Compensate for Local Anesthetic Cytotoxic Effects on Tenocytes: Morphine or Morphine Plus Dexamethasone May Be a Safe Alternative

Single-dose intra-articular morphine after arthroscopic knee surgery: A meta-analysis of randomized placebo-controlled studies

Targeting inflammation and wound healing by opioids

Analgesic efficacy of intra-articular morphine in experimentally induced radiocarpal synovitis in horses

Analgesic efficacy of the intra-articular administration of high doses of morphine in patients undergoing total knee arthroplasty

In Vitro Exposure to 0.5% Bupivacaine Is Cytotoxic to Bovine Articular Chondrocytes

Original ArticlesThe effects of morphine on human articular cartilage of the knee: An in vitro study*,**,★

Abstract

Section snippets

Methods

Results

Discussion

Acknowledgements

Eur J Pharmacol

Pain

Arthroscopy

Analgesic effect of intra-articular morphine after arthroscopic knee surgery

N Engl J Med

Intra-articular morphine for pain relief after knee arthroscopy

J Bone Joint Surg Br

Original Articles
The effects of morphine on human articular cartilage of the knee: An in vitro study*,**,★