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Intra-articular bupivacain plus opioid analgesics for chronic joint pain






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Concerns before Total Knee surgery

M. Salim and Waqas A.Kazi, Pain Clinic. Railway Hospital, Rawalpindi, Pakistan


Traditionally opioids are considered to exert their analgesic effect with in the central nervous system. There are receptors in joints also, which are sensitive to minimal doses of opioids. Khoury GF and colleagues reported 5 cases that were given intra-articular morphine for chronic joint pain with excellent results.

We have injected combination of local anasthetic and minimal doses of Pethedine (Nalbuphine) to see result in chronic osteoarthritic knee pain and other small joints pain. The results were compared with TENS (Trans-cutaneous Electrical Nerve Stimulation), Non Steroidal Ani-inflamatory Drugs (NSAIDs) and Intra-Articular Steroids. We have observed that twice- a week injection of lOmg Pethedine or 5mg Nalbuphine plus 10ml of 0.25% Bupivacain in a 70kg patient had much longer analgesic effect.

Key Words: Osteoarthritis; Intra-Articular Injection; Opioids


Recently evidence has begun to accumulate that potent analgesia can be elicited by activation of opioid receptors in peripheral tissues,especially in inflamed tissues. Small doses of morphine have been shown to markedly inhibit acute post-operative pain when injected intra-articularly after arthroscopic knee surgery.

When combined with local anaesthetic the action of opioid is much prolonged.

Till late, the traditional approach to the patients with osteoarthritic joint pain is either to administer NSAIDs, alone or alongwith TENS, or to manage with Steroids,oral or intra-articular. All these remedies have their limitations and side effects. Therefore, we have tried to evaluate the new regimen and have compared the results with the two conventional approaches.


We selected 60 patients from our Pain Clinic ranging from 40 to 60 years of age. Male to Female ratio was 1:1 ;Weight ranging from 55 to 80 kg. They were divided, into three groups. Group 1 included those who were already having NSAIDs and "TENS_NSAIDs" Group. Group 2 comprised of the patients who were getting Steroids, Orally or Intra-articularly_The "Steroid Group". The Group 3 included those patients who were for Intra-articular Opioids. The "OPIOID GROUP".

The NSAIDs Group received TENS daily alongwith NSAID up to the maximum pharmacological doses.

The Steroid Group received up to 6mg of Dexamethasone and 40mg of Depomederol intra-articularly once every three months or later depending upon the response of the patient.

The "Opioid Group" received biweekly intra-articular injections of lOmg of pethedine or 5mg of Nalbuphine plus 10ml of 0.25% Bupivacain.

Following parameters were compared:

  1. Onset of analgesia
  2. Duration of analgesia
  3. Quality of analgesia as indicated by joint mobility.
  4. Side-effects either observed or well documented in literature.
  5. The degree of analgesia by using Pakistan coin pain scale.

As most of the patients are not familiar with the commonly used pain scoring systems, we use coin scale that is the normal way of describing pain by our patients. It has previously been used in evaluation of pain in our patients and has yielded satisfactory data.


Group 1 (NSAIDs Group) required increasing doses of NSAIDs while the onset of analgesia remained constant, at about 2 hours. With TENS reduction in onset time by about 30 minutes was observed. Duration of analgesia varied with the choice of NSAID used, maximum being 12 hours. Improvement in joint mobility was sporadic and depended on the half-life of the agent used. However no absolute pain free interval was reported. Side effects included Gastric irritation requiring Antacids and H2 receptor antagonists.

In group 2, those patients who received oral steroids, the onset time was between 2-6 hours while with intra-articular steroids the onset of analgesia was delayed for up to 72 hours. With oral steroids the effect lasted for 24 hours and with intra-articular injection the beneficial effects were seen upto 3-6 months.

Quality of analgesia was much better as compared to group 1. Increased patient well being and enhanced physical activity confirmed this. Side effects of steroids are well documented and deserve a thorough consideration.

Group 3 patients had shown the most promising results. The onset of analgesia was much quicker" 15 minutes only. With three injections in 10 days, complete remission was observed for 12-18 months, average duration being 13 months. Only three of the 20 patients reported mild drowsiness.







30 min-2 hr.

UPTO 12hr.



6hrs-72 hr.

UPTO 6 months



15 minutes

12-18 months



Traditionally, it is believed that opioid analgesia is solely due to activation of receptors in central nervous system (1). Over the past 15 years potent peripheral actions of opioids have been discovered. Such effects primarily occur in inflamed but also in normal tissues(2). These effects were judged by standard pharmacological criteria(e.g., reversibility by antagonists, dose dependency and stereo specificity). All three opioid receptor types( mu, delta, and kappa) can be functionally active in peripheral tissues(3).

Opioid receptors have been demonstrated on peripheral terminals of thinly myelinated and unmyelinated sensory nerves in animals(4)(5) and in human(6). Opioid receptor messenger riboneucleic acid has been detected in dorsal root ganglion(7). When these neuronal opioid receptors are occupied by an agonist the excitability of nociceptive input terminal or the propagation of action potential is attenuated and the peripheral release of excitatory neuropeptides (e.g., substance p ) is inhibited. These events may account not only for anti-nociception but also for the anti-inflammatory actions of opioids in peripheral tissues(8).

It is rather more interesting to note that efficacy of peripherally applied opioids is much enhanced in the presence of inflammation. One possible explanation is that opioid agonists have easier access to neuronal opioid receptors because the perineurium is disrupted(2).In addition , previously inactive neuronal opioid receptors may undergo changes in inflammation milieu and be rendered active. At later stages of inflammation the peripherally directed axonal transport of opioid receptors in nerve fibres is enhanced which leads to an increase in their number(upregulation) on peripheral nerve terminals(7). Together these factors account for the dramatically increased efficacy of locally administered exogenous opioids in inflamed tissues.

Endogenous ligands of peripheral opioid receptors, opioid peptides( endorphins, enkephalin, and dynorphin) and their respective mRNAs have also been discovered in inflamed tissues. These peptides are produced by immune cells including T- and B-Lymphocytes, Monocytes and Macrophages(5). On release, these act on local opioid receptors to produce analgesia. Opioid peptides were detected in uninflamed human synovia(6) and following intra-articular administration of opioid antagonist Naloxone, patients with opioid containing synovitis had more severe pain after knee surgery(3).This shows that the endogenous opioid normally exert potent tonic pain control. They do not interfere with exogenous opioids and help to reduce tolerance so increase in dose is not required.

The fact that peripheral opioid effects are more pronounced in inflamed tissues is advantageous considering that the most painful conditions are associated with inflammation. Successful attempts have been made to develop opioids, which do not cross the blood-brain barrier. In our study, we have used Pethedine/Nalbuphine because preservative-free Morphine is not available in Pakistan.

We have found that intra-articular injection of Bupivacain plus Pethedine/Nubain had much longer duration of action, which can not be explained on the pharmacological basis of Local Anaesthetics alone. It is reasonable to believe that LA produce initial quick onset and opioid then produce more sustained action.

One of the major advantages of this technique is that the side effects are few and far between. The NSAIDs produce gastric disorders, bleeding diathesis, hepatic and renal damage. The steroids have well documented side effects like Diabetes Mellitus; fat degeneration; Cushing Syndrome; bleeding disorders and immunosupression.

Another major advantage of this technique is its cost-effectiveness. This can be a major consideration in developing countries.

To conclude, we have found combination of local-anaesthetic and opioid very effective and recommend that it may be tried as first line of treatment in management of osteoarthritic joint pain.


  1. Reisine T; Pasternak G; Opioid analgesia and antagonists. In J. G. Hadman A. Goodman Oilman and L.E. Limbird (eds.). Goodman and Oilman's "the pharmacological basis of therapeutics. New York, 1996 pp.521-5 5 5.
  2. Antonijevic I; Mousa SA; and Stein C; Perineurial defect and peripheral opioid analgesia in inflammation. J. Neurosci., 15(1995) 165-172.
  3. Stein C., Peripheral mechanism of opioid analgesia. Anaesth. Analg. 76(1993)182-191.
  4. Hassan AHS. Ableitner A., Stein C., and Herz A., Inflammation of rat paw enhance axonal transport of opioid receptors in the sciatic nerve and increase their density in the inflamed tissue. J. Neurosci., 55(1993) 185-195.
  5. Stein C., The control of pain in peripheral tissues by opioids; N. Engl. J. Med. 332(1995)1685-1690.
  6. Stein C., Pfluger M., Yassouridis A., Hoelzl J., Lehrberger k., Welte C., and Hassan AHS., No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. J. Clin. Invest.,98(1996)793-799.
  7. Schafer M., Imai Y., Uhl GR. And Stem C. Inflammation enhances peripheral u-opioid-receptor mediated analgesia, but not u-opioid receptor transcription in dorsal root ganglion. Eur. J. Pharmacol., 279(1995)165-169.
  8. Yaksh TL, Substance P release from knee joint afferent terminal; modulation by opioids,. Brain Res.,458(1988)319-324.
  9. Khoury GF., Garland DE., and Stein C., Intraarticular opioid-local anaesthetic combinations for chronic joint pain. Middle EastJ. Anaes; vol 72, 6(1994)579-85

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