Opioid with NSAIDs

An alternative strategy uses the combination of known drugs such as tramadol and acetaminophen, thereby targeting multiple components of the pain pathway (Silverfield et al., 2002). This combination of opioids with NSAIDs is a well-established strategy that is part of the WHO scale for treatment of chronic pain. 

Clinical use Paracetamol (Ameer and Greenblatt, 1977 Clissold, 1986) has analgesic and antipyretic properties, but no relevant anti-inflammatory action. It is used for the treatment of various mild to moderate pain conditions and to reduce fever. Paracetamol is one of the most popular analgesics as a single drug or in multi-ingredient preparations, often in combination with NSAIDs or weak opioids. 

The prior art expressly teaches one of ordinary skill in the art to combine an opioid with an NSAID.123 Furthermore, based on the prior art, a person of ordinary skill in the art of pain management would have had a reasonable expectation of success in combining hydrocodone, a narcotic analgesic, with ibuprofen, an NSAID. 

Contraindications fc>r nonsalicylate NSAID therapy are the same as those for aspirin (see Box 7-I).The formation of a gastric ulcer or erosion that may bleed profusely is a serious potential problem with NSAIDs. Consequently, the nonsalicylate NSAIDs should be avoided or used with great caution in patients with active peptic ulcer disease. NSAIDs may increase the risk of GI complications even when used in conjunction with low-dose aspirin for cardioprotection. In addition, because of potential crosssensitivity to other NSAIDs, the nonsalicylate NSAIDs should not be given to patients in whom aspirin or other NSAIDs have caused symptoms of asthma, rhinitis, urticaria, angioedema, hypotension, bronchospasm, or of symptoms of hypersensitivity reactions. Opioids, tramadol, or acetaminophen may be suitable alternatives for patients with known or suspected susceptibility. 

Even with the significant advances achieved in the discovery of new and more specific NSAIDs. they all have aceiling cffc ct on their ability to relieve all pain. It is becoming common practice to use combinations of the opioid drugs with NSAIDs to treat severe and intractable pain. These drugs are considered below in their various chemical categories. 

Clonitazene [ban. inn) (Ciba 19390 NIH 7586) is a benzimidazole derivative, an opioid receptor antagonist. Clonixin [inn, usan) (CBA 93626 Sch 10304) is a pyridinecarboxylic acid derivative, a CYCLOOXYGENASE INHIBITOR With NSAID ANALGESIC. ANTIINFLAMMATORY and ANTIPYRETIC activity. It is also used in the form of a lysine salt, lysine clonixinate also the dihydroxypropyl ester, clonixeril [inn, usan). 

Analogous to the relationship between systemic opioids and NSAIDs, intraspinal narcotics often are combined with local anesthetics. This permits the nse of lower doses of both agents. 

Acute pain is the presence of severe discomfort or an uncomfortable sensation that has a sudden onset and subsides with treatment. For example, a fractured bone causes acute pain since the uncomfortable sensation occurs suddenly when the bone is broken and subsides when the bone is immobilized in a cast. Pain associated with myocardial infarction (heart attack), appendicitis, and kidney stones are also examples of acute pain. Acute pain can be treated with NSAIDs or opioid analgesics. 

NSAIDs are often administered with opioids because they usually reduce the opioid requirements and some of the opioid-induced Averse effects. Enhanced pain relief has been reported with various combinations including dextromethorphan with ketorolac or tenoxicam, oxycodone with ibuprofen, and tramadol with ketorolac without increased adverse effects. See also coxibs , (p.l79). However, cases of respiratory depression have been reported, see Morphine below. Myoclonus has been reported with high does of morphine administered with NSAIDs, see C3pioids Morphine + Miscellaneous , p.l90. 

Data from studies on cancer pain treated with combination opioid plus NSAIDs are equivocal. NSAIDs with opioids have shown no improvement or hmited improvement in pain control. However, the medications have not been approved for long-term therapy, which probably would be required for treatment of cancer pain. Further studies are needed to determine safety and efficacy of combination drugs in this patient population. 

Studies on treatment of chronic non-malignancy pain, such ash chronic low back pain, showed a measmable improvement in symptoms when patients took opioid plus NSAID combination drugs versus the drugs alone. As with cancer pain, the duration of treatment in the studies was short (8 days). It is reasonable to suspect that longer duration of therapy would be necessary in these patients. Therefore, further studies are needed to determine the safety and efficacy of longer duration therapies in this patient population. 

Absolute contraindications for both opioids and NSAIDS include hypersensitivity reactions, such as development of shortness of breath, severe rash, etc. Oxycodone and hydrocodone are contraindicated in patients with risk for significant respiratory depression. Because of the inhibition of GI motility by narcotic medications, oxycodone and hydrocodone are contraindicated in the setting of paralytic ileus. 

There are numerous relative contraindications to combination opioids and NSAIDs. They include but are not limited to a past medical history of GI bleeding, history of chronic renal disease, a history of abuse of drugs or other substances, a history of seiziu es related to head trauma, brain tumor, or increased intracranial pressure, or documented urinary retention with use of narcotics. 

Combination opioids and NSAIDs are provided in oral preparations. Vicoprofen is supplied as 7.5 mg hydrocodone plus 200 mg ibuprofen tablets. For acute moderate to severe pain 1 tablet should be taken every 4-6 hours. Ibudone is supplied as a 10 mg/200 mg tablet, while Reprexain is manufactured as 2.5 mg, 5 mg or 10 mg/200 mg combination tablets. Each is commonly prescribed as 1 tablet every 4-6 hours for acute moderate to severe pain. Combunox is 5 mg oxycodone and 400 mg ibuprofen, every 6 hours, with a maximum of four tablets daily. Combunox may offer advantages over other preparations since it contains a higher dose of ibuprofen (400 mg) equivalent to doses commonly prescribed for acute pain. It is recommended that therapy be limited to 7-10 days or less. 

Non-opioid analgesics (NSAIDs, COX-2 inhibitors, APAP), including celecoxib, are part of the World Health Organization s (WHO) analgesic ladder for the treatment of mild to moderate cancer pain. There are no celecoxib dosing guidelines for the treatment of somatic pain associated with cancer. 

When used as monotherapy, IV acetaminophen does not cause excessive sedation, biliary spasm, respiratory depression, nausea, vomiting, ileus, or pruritus associated with opioids, nor the harmful cardiovascular, renal, gastrointestinal, and hematological effects associated with NSAIDs and COX-2 inhibitors. 

Ketamine may be ideal to treat post-operative pain after adenotonsillectomy. It avoids the feared risks of bleeding with NSAIDs and respiratory depression with opioids. Ketamine at a dose of 0.5 mg/kg IV reduces post-operative pain and need for other analgesics. Peritonsillar infiltration at the same dose has a similar effect to the intravenous dose. The time of administration either before the start or the conclusion of surgery has no bearing on the analgesic effect. If prolonged pain is anticipated a ketamine infusion of 0.3 6 mg/kg per h can be started after the administration of a loading dose of 0.5 mg/kg. 

It is mandatory to set up a realistic goal prior to initiating pain management. Duloxetine, as an adjuvant analgesic, may contribute to pain relief gradually but not instantaneously. Previous studies have demonstrated mild to moderate pain relief in patients who responded to duloxetine treatment. The efficacy and timeline with duloxetine were quite different than analgesics such as opioids or NSAIDs that were not FDA approved for DPN and/or fibromyalgia. 

As used for multimodal analgesia cyclobenz-aprine (Flexeril), carisoprodol (Soma), oral steroids, opioids, and NSAIDs can all be used in combination therapy with caution, based on the severity and onset of symptoms. 

Low-dose opioid analgesics (e.g., oxycodone) may be useful for patients who experience no relief with acetaminophen, NSAIDs, intraarticular injections, or topical therapy. 

Tramadol with or without acetaminophen has modest analgesic effects in patients with OA. It may also be effective as add-on therapy in patients taking concomitant NSAIDs or COX-2 selective inhibitors. As with opioids, tramadol may be helpful for patients who cannot take NSAIDs or COX-2 selective inhibitors. 

Agents Acetaminophen or NSAID combinations with opioids Adjuncts Tricyclic antidepressants Anticonvulsants Radiopharmaceuticals (Bone pain) Acetamnophen (See above) Opioids Titrate Amitriptyline 10-50 mg Imipramine 10-50 mg NSAIDs (See above) Gabapentin (Neurontin) 3.6 g... 

Whenever bone pain is present, consideration of an NSAID with opioid should be routine. 

The combination of an opioid and nonopioid oral analgesic often results in analgesia superior to monotherapy and may allow for lower doses of each agent. An NSAID with a scheduled opioid dose is often effective for painful bone metastases. 

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