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5 Articles in Volume 0, Issue #1
Chronic Tension Headache
Corticosteroid Use in Pain Management
Fibromyalgia Syndrome & Surface Electromyography
Intraarticular Mechanisms for Pain Control
Pharmaceuticals in the Pipeline - Anti-rheumatic Drugs

Intraarticular Mechanisms for Pain Control

Postoperative pain control after surgery of the joint can be obtained through the use of intraarticular injection of local anesthetics and opioids.

The observation that patients who had arthroscopic knee surgery under local anesthesia seem to have less postoperative pain than patients with comparable procedures performed under general anesthesia lead to investigations to explain this phenomenon. A similar favorable effect was noted after general anesthesia if the intraarticular local anesthetic solution was injected as a part of the arthroscopic surgery. The idea that postoperative analgesia could be achieved by injection of local anesthetics and/or opiates into the joint prior to surgery was considered a possible explanation.

Clinical Studies of Intraarticular Analgesia

The first clinical study of intraarticular pain control was reported by Stein.1 There were 52 patients with morphine, saline and naloxone injected into the intraarticular space at the conclusion of surgery. The dose of morphine was very small (1mg) and provided complete pain relief for up to 18 hours after intraarticular arthroscopic surgery of the knee. This pain control was not achieved by intravenous morphine either in quality or duration and was eliminated when naloxone was injected into the intraarticular space. A dose of 0.5 mg of morphine was analgesic but not as effective as 1.0 mg. Khouri2 evaluated morphine, bupivacaine or a combination after surgical arthroscopy and found the combination to be superior to either element alone, when injected at the conclusion of surgery. Allen3 also looked at surgical arthroscopy, and found the combination of bupivacaine (0.125 percent), morphine and epinephrine to be the best choice, with nearly complete pain control for up to 24 hours. De Andres4 compared postoperative intraarticular bupivacaine or morphine with femoral nerve block and found the intraarticular injection to provide comparable analgesia to femoral nerve block. With non-arthroscopic ACL repair, intraarticular morphine was significantly better than saline administered at the conclusion of surgery, injected by needle away from the wound after the joint was sealed and the drain clamped.5-6

“Intraarticular local anesthetics alone have been shown to have an analgesic effect postoperatively.”

Intraarticular local anesthetics alone have been shown to have an analgesic effect postoperatively. Gyrn7 reported an improvement of pain control with increasing doses of bupivacaine and epinephrine given as the sole anesthetic for diagnostic arthroscopy. The favorable effect is not limited to bupivacaine, with prilocaine plus epinephrine being superior to saline for pain control administered into the intraarticular space at the conclusion of surgical arthroscopy.8 Badner injected 0.5 percent bupivacaine into the knee joint at the completion of total knee replacement and found analgesia, reduced opioid requirements and some improvement in early joint mobility.9 Badner also added epinephrine to intraarticular bupivacaine and demonstrated analgesia after total knee replacement, which did not improve with the addition of morphine.10 Although some pain relief could be demonstrated with intraarticular bupivacaine without epinephrine, intraarticular morphine was superior.11-12 For limited procedures, intraarticular lidocaine was equivalent to femoral nerve block.13

Intraarticular analgesia has also been demonstrated with other substances besides opioids and local anesthetics. Badner demonstrated an analgesic effect with epinephrine,10 which was also noted by Gatt.14 Other intraarticular analgesic effects have been demonstrated with NSAIDs,15-17 neostigmine18 and steroids.19

Raja,20 Bjornsson21 and Heard22 report inconclusive data although study design description does not allow evaluation of surgical technique variation that could explain the conflicting outcome. In particular, it is impossible to tell if the solutions were injected after the knee was watertight. Whitford demonstrated a beneficial effect of intraarticular injection during tourniquet inflation, which did not occur when the injection occurred immediately before tourn-iquet deflation.23 Reuben could not demonstrate an additional benefit after minor arthroscopic surgery from intraarticular morphine when it was added to intraarticular bupivacaine and systemic keterolac,24 possibly because bupivacaine combined with systemic keterolac was completely analgesic.

Cellular Mechanisms for Intraarticular Pain Control

Although it is widely accepted that opioids produce analgesia by activation of opioid receptors at the spinal and supraspinal levels, there is increasing speculation about activity of opioids at peripheral sites. Animal studies suggest the possibility of a direct effect in peripheral tissue. Joris25 reported a study involving rats and a standard inflammatory process. After injecting an irritating agent into both paws and allowing the correct interval for development of hyperalgesia, either fentanyl or another opioid agonist was injected into the inflamed site of one paw and saline into the other. Significantly less hyperalgesia evolved in the opioid injected paw. Ferreira26 found a similar effect, which was not reversible by naloxone after morphine. Calcium ion movement was shown to be related to the development of hyperalgesia and analgesia during the same experiments.27 Stein28 was able to demonstrate peripheral opioid receptors in rats with acute inflammation. These receptors were induced by inflammation, since they were not present in normal (non-inflamed) tissues.

The magnified effect of small doses of opioids in the intraarticular space suggests a specific receptor or novel mechanism of action. Martinez29 investigated the influence of B-endorphin in the knee joint of cats. Experimental arthritis was induced with hydrochloric acid and measured by uptake and extravasation of intravenously administered Evans blue dye. B-endorphin, injected into the knee both before and after the injury, dramatically reduced the level of arthritis that resulted compared to the control (saline treated) knee. Although the effect is direct, it is not a local anesthetic action, since peripheral nerves of cats showed no alteration of the speed of conduction or the frequency or amplitude of their compound action potentials when exposed to opioid agonists.30 Various opioids prevent the expression of opioid receptors in a standard animal inflammation model and after the expression of these receptors in an established inflammatory zone, injection of these opioids had an analgesic action that resembles a receptor agonist activity.31 This intraarticular action of opioids may help to explain the favorable effect of intraarticular morphine in the suppression of chronic pain associated with intraarticular arthritis in humans.32 When chronic arthritis is induced in cats, there is a huge increase in expressed opioid receptors in the intraarticular space and increased opioid binding.33 The clinical effect of adrenergic substances and neostigmine is also supported by animal work that demonstrates analgesia associated with neurotransmitter manipulation in the intraarticular space.34

The mechanism of substances injected into the intraarticular space prior to insult having a magnified analgesic effect after the insult has also been evaluated. Intraarticular recording of the activity of small afferent nerve fibers has yielded considerable information. Receptor activity occurs at a baseline level during normal range of motion of the cat knee joint. When an inflammatory state is induced, receptor activity is 400-500 percent-increased.35 In another experiment,36 the receptors that were silent during range of motion became active immediately after injury. The work is interpreted to mean that receptors within the intraarticular space are multi-modal and can become nociceptive when exposed to injury or the tissue chemical mediators of injury (i.e. prostaglandins or substance P). A spinal cord component also contributes to hypersensitivity at the spinal cord level, which is expressed after inflammation, but not before.37 The contribution of local anesthetics to intraarticular analgesia is suggested by the ability of local anesthetic to block the secretion of substance P and prevent intracellular calcium movement in response to nociceptive signals.38

“The magnified effect of small doses of opioids in the intraarticular space suggests a specific receptor or novel mechanism of action.”

Clinical Significance of Intraarticular Injection for Postoperative Pain Control

The balance of evidence presently available strongly suggests that intraarticular injection of local anesthetics, opioids, adrenergic agents and other substances provides pain relief after intraarticular surgery. These agents provide a quality and duration of analgesia that exceeds their impact when administered by a parenteral route. The mechanism of this effect is probably related to the suppression of the inflammatory response to surgical insult and the decrease or prevention of hypersensitivity.

These favorable effects are even more significant when considered in the context of the side-effect profile. Analgesia occurs without systemic effects or any of the traditional opioid side-effects.39 Despite large volumes of local anesthetic in some of the reports, the plasma levels of the agent are extremely low.40 The only reported exception is local anesthetic toxicity that occurred when intraarticular bupivacaine was used in the presence of intraarticular fracture.41

Although the majority of work reported is about intraarticular injection of the knee, there is some evidence that other intraarticular spaces may also have the same potential. Specifically, intraarticular injection of the shoulder may contribute to analgesia after open or arthroscopic shoulder surgery.42-43 In conclusion, intraarticular injection after joint surgery can accomplish pain control with a low side effect profile, and long-duration of analgesia. Local anesthetics, opioids and a variety of other substances can provide this effect. Intraarticular analgesia probably occurs because of modification of pain receptors within the joint or interference with nociceptive transmission.

Last updated on: December 27, 2012
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