For all their pain-relieving efficacy, opioid medications are limited in that they do not control all pain - and their side effects are well-known. Non-opioid medications occupy a critical place in the selection of analgesic options, but non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors also have benefits and drawbacks. Here's what you need to know.

Drug mechanisms
Anti-inflammatory medications are the first-line adjunct to opioids after surgery. To understand why physicians prescribe these drugs to control opioid-resistant or mild pain not requiring opioids, it helps to understand some of the pain mechanisms involved.

Inflammation is one of the principle physiological processes in increased pain after surgery or trauma. After tissue damage, chemicals called prostaglandins form out of the products of damaged cells. Prostaglandins lower the response threshold of pain-nerve endings, making touch and movement painful. For example, when an individual develops redness from sunburn, prostaglandins are responsible for the pain that comes from touching the skin, whereas normally skin tissue must be cut, crushed or burnt to trigger pain. This mechanism is similar to the prostaglandin formation in joints occurring with rheumatoid arthritis, which causes pain when joints move or experience pressure.

When are they used?
The classic model for post-op adjunctive-analgesics use comes from dental surgery. Molar extraction is a great example of a situation in which opioids are actually less effective and have more complications than anti-inflammatory drugs. Dentists and oral surgeons often mistakenly give acetaminophen and codeine (Tylenol 3) or acetaminophen and hydrocodone (Vicodin) in such cases, when in fact an NSAID or COX-2 inhibitor would provide much better analgesia with fewer problems.

This is not the necessarily the case for other types of surgery. Many forms of surgery produce pain that, while partially responsive to anti-inflammatory medications, still requires opioids for adequate pain relief.

Given the problems with opioids, it's probably best to adopt a multi-modal analgesic approach for post-op pain. Multi-modal analgesia is the practice of controlling pain by combining analgesics that work by different mechanisms of action. Norco or Vicodin (both containing hydrocodone and acetaminophen) are examples of this, because both components of these drugs produce analgesia, but by different mechanisms.

The best approach to multimodal analgesia is to follow World Health Organization guidelines, which means starting with non-opioid approaches, then adding opioids as needed. For example, begin with a COX-2 inhibitor or NSAID, if appropriate, then add opioid analgesia.

This is not always possible or reasonable. For example, patients with compromised renal function probably should not receive NSAIDs or COX-2 inhibitors, which can injure the kidneys. Patients with normal renal function do not have this issue. Also, patients in whom perioperative bleeding in any form is a concern - in plastic surgery, for example - probably should not receive traditional NSAIDs because they inhibit platelets. The COX-2 inhibitors, which are a newer form of anti-inflammatory medications, do not inhibit platelet function and therefore can be used in situations with increased bleeding. COX-2 inhibitors are also safe for children.

Currently there are three COX-2 inhibitors, all in oral form, available in the United States. One is valdecoxib (Bextra), which is approved for chronic pain but not indicated for acute pain. (An IV form of Bextra, called parecoxib, is undergoing FDA evaluation.) Rofecoxib (Vioxx) is approved in the United States for acute pain, but is limited to five days of use in this dosing because of potential cardiovascular problems, edema and hypertension. The third is celecoxib (Celebrex), which is remarkably safe, but doesn't work as quickly as Bextra or Vioxx.

NSAIDs, on the other hand come in parenteral and oral versions. Ketorolac (Toradol), for example, can be given via IV immediately before surgery, during the procedure, or post- operatively in cases where the patient cannot take pills. Ketorolac affects platelets, and its oral form can cause significant stomach irritation, so its use is limited to five days.

The COX-2 inhibitors therefore can be given pre-operatively without concern for bleeding, and their effects and benefits remain active in the immediate post-op period.

These adjunctive medications can - and perhaps should - be used for all surgical procedures whenever it is safe. The primary limitations of COX-2 inhibitors and NSAIDs are renal dysfunction, concerns with bleeding (with the NSAIDs), and in select cases where difficulty with bone growth after orthopedic procedures is a concern (both NSAIDs and COX-2 inhibitors demonstrate weak but measurable inhibition of bone growth). Currently, only lumbar fusion has been shown to have a problem with NSAIDs; COX-2 inhibitors are not known to affect lumbar fusion outcomes.

How do they work?
Traditional thought is that these drugs relieve pain by reducing inflammation at the surgical site. More recent data show this probably is not the case, and that in fact these drugs primarily produce their effects in the brain and spinal cord, with the additional benefit of synergistic action at the surgical site. This dual effectiveness in the periphery and central nervous system gives NSAIDs and COX-2 inhibitors a significant advantage over opioids, which work almost exclusively on the central nervous system in treating pain.

Ibuprofen (Motrin) is the most commonly used NSAID in the United States. It is remarkably safe and effective, and is available in prescription and over-the-counter (OTC) strengths. Naproxen (Aleve) is another commonly used NSAID, also available OTC in its lower dosage and which also has a well-established safety profile. Both of the medications, however, have significant effects on platelet function and may be problematic after many outpatient procedures due to bleeding concerns.

Administration timing
It's best to give any pain medication before the patient experiences pain, whether it's before of after surgery. Called pre-emptive analgesia, this greatly affects both patient satisfaction and the course of recovery. Studies from the 1970s and '80s said it was critical to give pain meds before making the incision, but more recent clinical studies refute this.

For example, if a patient receives a spinal anesthetic, it doesn't matter if the pain medication is given before the surgeon cuts or after the surgeon completes the surgery, as long as it happens before the spinal anesthetic wears off and the patient can feel pain.

A patient's recall of pain depends almost entirely on the most severe pain they experience, not average pain level. Therefore, it's better to prevent high pain peaks than to focus on stopping all pain throughout the perioperative period.

When dealing with incident pain, preventing such peaks is difficult to do with opioids alone. In fact, incident pain is best prevented with medications, such as NSAIDs, COX-2 inhibitors and possibly gabapentin (Neurontin), that do not cause side effects like sedation or nausea.

Other alternatives
Acetaminophen is often included in the NSAID classification, although no peripheral anti-inflammatory actions have been identified. Acetaminophen appears to act in the central nervous system to inhibit prostaglandin formation. Several studies have demonstrated it has less analgesic effect in the peripheral tissues than NSAIDs and COX-2s.

More recently, other medications have been examined for potential roles in treating opioid-resistant pain or in enhancing opioid analgesia after surgery. One is gabapentin, originally designed as an anti-seizure medication. Although not indicated for acute pain, a handful of studies have shown that, when given in a large dose before surgery, gabapentin can significantly reduce the post-op opioid requirements. Likewise, gabapentin enhances the quality of analgesia in such cases. The drug is not metabolized and therefore has minimal interactions with other medications. Its primary side effect, sedation, could cause a problem for outpatient procedures.

Gabapentin's role in outpatient surgery needs to be better clarified. But it seems promising. Keep in mind that using gabapentin as an analgesic medication is an off-label indication. Regulators recently took punitive action against the drug's maker, Warner Lambert, for promoting gabapentin for off-label uses. In fact, such uses originated with physicians.

Which meds should be on hand?
When physicians ask a hospital or surgical center administrator to have a particular COX-2 inhibitor or NSAID available, you must remember that molecular, biological and genetic differences among patients will lead to different responses to the medications. The enzyme that is stopped by the COX-2 inhibitors and NSAIDs has many isoforms within and among persons, which accounts for varied patient responses.

A 1991 study demonstrated that a typical rheumatology practice needs between 10 and 15 anti-inflammatory drugs to cover all patients. Fewer than that may be required to control acute post-op pain. It is probably wise to have on hand at least a few of the nonsteroidal anti-inflammatory drugs and COX-2 inhibitors; it is certainly wise to have at least one or two - or probably all three - of the COX-2 inhibitors available perioperatively given the issues with post-op bleeding.

Clinical differences
There are significant and noteworthy clinical differences among the various adjuvant non-opioid pain medications. Ketorolac and all other NSAIDs inhibit platelets. Ketorolac also can increase the risk of gastrointestinal ulceration compared with other medications.

The COX-2 inhibitors have a reduced risk of GI ulceration and do not affect platelets. But like the nonsteroidals, they can cause problems with the kidneys, especially in patients with borderline renal function. In those isolated cases where bone healing may be problematic - specifically lumbar fusion - COX-2 inhibitors show the same problems as those seen with the nonsteroidals.

As for analgesic efficacy, there is no clinical evidence that one NSAID is better than another. By now, the COX-2 inhibitors have been studied extensively for post-op use. The drug companies note that Celebrex and Bextra have sulfonamide groups, so supposedly you have to be careful using these medications in patients with sulfa sensitivity. Yet, they have the same sulfonamide groups as the diuretics, with which such sensitivity has not been a problem. The caution recommended with the use of Celebrex and Bextra in potentially sensitive individuals is probably more of a medicolegal issue than a clinical concern.

Then there is the issue of whether Vioxx, if used for prolonged periods, is associated with an increased heart attack risks. Used for just a few days perioperatively, it's probably not a concern. Vioxx does have a higher incidence of edema in the short term compared with other COX-2 inhibitors.

Expect to see more COX-2 inhibitors coming on the market. Novartis is due to come out with one, and Merck is working on one of its own. More will likely come in time.