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Keywords:

  • analgesia;
  • combination therapy;
  • efficacy;
  • pain;
  • synergy;
  • tolerability

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANALGESIC CLASSES
  5. COMBINATION ANALGESICS
  6. CONCLUSIONS
  7. References

No single analgesic agent is perfect and no single analgesic can treat all types of pain. Yet each agent has distinct advantages and disadvantages compared to the others. Hence, clinical outcomes might be improved under certain conditions with the use of a combination of analgesics, rather than reliance on a single agent. A combination is most effective when the individual agents act through different analgesic mechanisms and act synergistically. By activating multiple pain-inhibitory pathways, combination analgesics can provide more effective pain relief for a broader spectrum of pain, and might also reduce adverse drug reactions. This overview highlights the therapeutic potential of combining analgesic medications with different mechanisms of action, particularly a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen with an opioid or tramadol.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANALGESIC CLASSES
  5. COMBINATION ANALGESICS
  6. CONCLUSIONS
  7. References

The use of a combination of oral analgesics vs. an individual agent offers several potential benefits. Combining analgesics into a single product may facilitate prescribing and compliance by reducing the total number of medications that a patient must take to manage pain. Combining products with different mechanisms of action may also provide multimodal coverage of a broad spectrum of pain and, in addition, enable the individual agents potentially to act in a greater than additive (synergistic) fashion. Furthermore, in terms of safety, lower doses of each individual analgesic, used in the combination, may result in a lower incidence of individual adverse events.

The American Geriatrics Society (AGS) (1) and the American Medical Directors Association (AMDA) (2) recommend combining analgesics for elderly patients and long-term care patients, respectively. The usefulness of combination pharmacotherapy for such patients has been recognized in most diseases for which medications are a mainstay of therapy, including hypertension, congestive heart failure, diabetes, HIV, asthma, dyslipidemia and coronary artery disease. Given the multiple pathways involved in the body’s perception of pain (3), combination therapy is well suited for pain management, and has been recommended by the World Health Organization (WHO) (4), the American Pain Society (APS) (5) and the American College of Rheumatology (ACR) (6).

This overview is not intended fully to describe the pharmacology of each analgesic, but rather to highlight the therapeutic potential of combining medications with different mechanisms of action, particularly a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen (APAP) with a centrally acting drug to influence the pain pathway at multiple sites. Figure 1 depicts typical sites of action for several analgesic classes. Excellent reviews have been published for each analgesic class, and the reader is directed to those articles for more detailed information on a particular medication (7[8][9][10][11]–12). It should be emphasized also that not all combinations or all dose ratios of a combination lead to an enhanced analgesic effect or to reduced adverse events. Each combination and each dose ratio needs to be evaluated individually.

image

Figure 1.  Major site(s) of action of analgesic classes.

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ANALGESIC CLASSES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANALGESIC CLASSES
  5. COMBINATION ANALGESICS
  6. CONCLUSIONS
  7. References

Traditional nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are among the most widely used medications. Given their efficacy in managing fever, mild to moderate pain and, at higher doses, inflammation, such widespread use is generally appropriate. Numerous prescription NSAIDs are available, but aspirin and ibuprofen are two non-prescription NSAIDs that contribute significantly to the use of this class of medications. It has been estimated that 20–30% of Americans use an NSAID each year, and 1–2% use NSAIDs every day (13).

The generally accepted mechanism of action of NSAIDs is that they attenuate prostaglandin synthesis by inhibiting cyclooxygenase (COX) enzymes (14), although some central action has been reported (15). NSAID side-effects, however, are often related to COX inhibition, which greatly limits their use (16). The side-effects are primarily gastrointestinal, haematological and renal. NSAIDs cause a localized irritation of the gastric mucosa (17). Higher doses or prolonged use may cause serious erosive gastritis and gastric haemorrhage due to a decrease in the amount of prostaglandins PGE2 and PGI2. Risk factors for developing gastropathy from NSAID use include a history of peptic ulcer disease or gastric bleeding, continued use of alcohol, and increasing age (18). The haematological effects of NSAIDs result from their inhibition of platelet aggregation. Because of this effect, all NSAIDs need to be used with caution in patients at risk for GI bleeding. Nephrotoxicity from NSAIDs is rare in healthy patients because both renal blood flow and glomerular filtration do not depend on prostaglandin levels, but the risk of nephrotoxicity increases for patients who are volume depleted, who have congestive heart failure, or who have hepatic cirrhosis (19). Serious idiosyncratic reactions to NSAIDs that are not related to prostaglandin inhibition are rare.

COX-2 NSAIDs

COX-2–selective NSAIDs have recently received much attention from clinicians, scientists, patients and the media. As their name suggests, these agents are selective for the COX-2 enzyme, which is thought to be responsible more for pain and inflammation, whereas the COX-1 isoform more commonly provides homeostasis in the intestines, kidneys and elsewhere (20). As a result, COX-2 NSAIDs are less likely to cause gastric ulceration, but they may inhibit healing of previous ulcers and therefore should not be used in patients with a history of GI ulcers, particularly NSAID-induced ulcers (20).

Acetaminophen

Acetaminophen (paracetamol) has been a mainstay for pain relief and fever control since its approval for use as an analgesic in 1960 (9). Even though acetaminophen has been available for several decades, the mechanism of action by which it elevates the pain threshold is not understood. The experimental evidence converges on two possibilities: an effect at the local site of injury (peripheral action), and an effect at some level, spinal or supraspinal, of the central nervous system (central action). The peripheral action would presumably be related to inhibitory modulation of peripheral mediators of pain. Some suggestions include inhibition of nitric oxide synthase (21), reversal of the hyperalgesia induced by NMDA (N-methyl-D-aspartate) or substance P (22, 23), decrease of spinal PGE2 release (24) or an effect on spinal cord 5-hydroxytryptamine (5-HT; serotonin) (25, 26). The latter effect would have to be indirect, as we found that acetaminophen does not inhibit constitutive or inducible nitric oxide synthase (unpublished data) or bind to known 5-HT receptors or to 5-HT neuronal reuptake sites (27). Part of the problem in elucidating the mechanism of acetaminophen may be due to the approaches taken, which have largely focused on a single pathway or site of action. In contrast to these approaches, our recent work has been directed toward dual site studies. This approach has led to the discoveries of three new properties of the mechanism of acetaminophen: (i) marked ‘self-synergy’ that results from spinal-supraspinal administration (28), (ii) the contribution of a descending endogenous opioid component (28) and (iii) pronounced and surprising synergy with phentolamine (29).

The side-effects of therapeutic use of acetaminophen are minimal. Unlike NSAIDs, it does not significantly inhibit prostaglandins and hence does not produce GI irritation or inhibit platelet aggregation. A serious adverse effect is hepatotoxicity, which can occur with large doses (10–15 g), when glutathione stores are depleted and a toxic metabolite of acetaminophen is allowed to accumulate (30). Unwitting use of multiple acetaminophen preparations simultaneously can cause accidental overdose. Hepatotoxicity typically does not occur in therapeutic doses (≤4 g/day), but alcohol intoxication has been shown to predispose patients to hepatotoxicity at normal acetaminophen doses (31).

Opioids

The use of opium, opiate extracts (e.g. morphine and codeine) and opiate-like substances (opioids) originated more than 1000 years ago, and morphine was synthesized almost 200 years ago (32). Opioids are the most powerful pain relievers, and therefore traditional opioid analgesics remain the drug of choice for the medical treatment of severe acute pain syndromes and for progressive severe chronic illnesses.

An understanding of the mechanism of action of opioids has only become possible since the identification of endogenous opioid-like peptides and receptors in the early 1970s (33). Three major structurally and pharmacologically distinct opiate receptor types (μ, δ and κ) and their subtypes are located throughout the body, both in the central and peripheral nervous system. Analgesia is thought to primarily involve opioid receptors in the brain and spinal cord (32). The most common side-effects seen with opioid therapy are constipation, nausea, vomiting, sedation, itching and respiratory depression (5). Although most adverse effects occur at a higher dose than is required for analgesia, some effects, such as constipation, commonly occur at therapeutic doses. Tolerance and physical dependence may also occur when using opioids over long periods of time (more than 2–3 weeks of continuous administration). Fortunately, many of these unwanted effects can be treated or prevented while maintaining adequate analgesia for the patient. Unfortunately, because of misunderstandings or unfounded apprehension about the possibility of tolerance or physical dependence, addiction, fear of professional or regulatory censure, or litigation, physicians are frequently reluctant to prescribe these important drugs in sufficient doses to relieve pain (34).

Tramadol

Just as acetaminophen shares some, but not all, the characteristics of NSAIDs, tramadol shares some, but not all, the characteristics of opioids. Tramadol was initially described as a traditional opioid; however, as shown in Table 1, tramadol has low affinity for μ-opioid receptors, more akin to the non-opioid imipramine than the opioid codeine (35). The M1 metabolite of tramadol binds μ-opioid receptors more strongly than the parent drug, and an opioid component contributes to tramadol-induced antinociception (animals) and analgesia (humans). However, because the opioid antagonist naloxone does not reverse all of the antinociceptive (35) or analgesic (36) effects of tramadol, additional mechanisms must contribute significantly to its analgesic effects. Several studies have shown that tramadol inhibits re-uptake of serotonin and norepinephrine, which synergistically enhances the opioid mechanism of action (35, 37, 38). This binary mechanism of action may explain the reduced incidences of abuse (39) (tramadol is a non-scheduled drug), respiratory depression and other adverse opioid effects relative to traditional opioids (35, 37). It may also explain why tramadol is effective in opioid-resistant chronic pain states (40, 41) and other painful conditions (42[43][44]–45).

Table 1.   Relative binding of centrally acting analgesics at μ-opioid receptors Thumbnail image of

Adjunctive therapies

In the past few years, knowledge of the neurophysiology, biochemistry and modulation of pain transmission has expanded at an increasing rate. Recently, numerous compounds have been studied to identify novel analgesic properties, including antidepressants (46, 47), anticonvulsants (48) and clonidine (49, 50). Because current therapy for pain relief is inadequate for some patients, and chronic pain is difficult to treat, the search for new analgesic compounds or therapies will continue.

COMBINATION ANALGESICS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANALGESIC CLASSES
  5. COMBINATION ANALGESICS
  6. CONCLUSIONS
  7. References

The combination of two analgesic drugs has the potential to overcome tolerability, efficacy and time-to-onset limitations of the component drugs and, in certain cases, synergistically to increase their analgesic effect. Combining analgesics with different mechanisms or sites of action, for example, can allow for reduced doses of the component drugs, reducing overall adverse effects with comparable analgesia. Likewise, combining short-acting and long-acting agents can result in both shorter onset and longer duration of analgesia.

The advantages of combining analgesic drugs has been recognized for almost a century, although until recently the experimental evidence has been lacking or inadequate, mainly due to limitations in study design and the ongoing difficulty in accurately assessing pain. Measuring synergistic interactions between drugs has also been difficult, particularly as incremental reductions in pain are not readily measurable, although models such as the isobologram are useful for analysing a range of combination ratios over which synergy occurs (51, 52). New statistical analyses and pharmacological modelling techniques, however, are becoming available (51). These analytical methods are crucial for accurately comparing the efficacy of an analgesic combination with that of each individual agent. It is important that these evaluations be made. For example, many well-known analgesic combinations have never undergone preclinical or clinical scrutiny for evidence of statistically enhanced analgesia or reduced adverse effects at the doses or dose ratios used clinically. For chronic administration it is also important to know the relative pharmacokinetic disposition of the constituent drugs. Repeat dosing of a combination might lead to a build-up of an agent beyond the beneficial dose ratio or even into toxic ranges.

Numerous clinical studies of oral analgesics have documented the benefits of combining analgesics (Table 2) (53[54][55][56][57][58][59]–60). However, the adverse effect profile of high-dose aspirin reduces its usefulness in combination therapy, so increasing emphasis has been placed on acetaminophen combinations. Adding a NSAID to acetaminophen has been shown to improve efficacy in acute pain states (61); however, the additional benefit of this combination must be weighed against the increased toxicities possible with long-term NSAID use. A recent trial in paediatric patients reported that there is no evidence to support combining these two drugs (62). Although combining acetaminophen with a COX-2 NSAID may be relatively safe for long-term use, the efficacy of this combination has not yet been studied.

Table 2.   Studies supporting the use of combination analgesics Thumbnail image of

Only one oral NSAID–opioid combination (ibuprofen/hydrocodone) that has been shown to be effective is currently approved for use in the US (58, 63). However, the combination of an NSAID with other opioids has been shown to be effective in dental pain (ibuprofen/oxycodone) (56), postoperative pain (ibuprofen/codeine) (64), osteoarthritic pain (any NSAID with oxycodone) (65) and other forms of pain. Long-term toxicities of both NSAIDs and opioids suggest that these combinations are best suited for acute pain states, although combining an opioid with a COX-2 NSAID may partially address this concern. However, no studies of such combinations are yet available, and the only commercially available combination, ibuprofen/hydrocodone, is not indicated for chronic pain management.

Based on extensive evidence of their efficacy, opioid–acetaminophen combinations are recommended in the WHO analgesic ladder for moderate to severe forms of pain (4). In 1999, nine of the top 200 drugs prescribed (including generics) in the United States were combinations of an opioid (hydrocodone, codeine, propoxyphene or oxycodone) and acetaminophen (66). Interestingly, clinical use of such combinations for some post- operative pain often involves the use of doses of the components that individually produce effective analgesia, yielding relatively modest gains in analgesic efficacy without significant decrease in adverse effects. For example, a meta-analysis published in this journal (67) of the use of acetaminophen combination with codeine for postoperative pain (e.g. dental surgery, episiotomy and uterine cramp), reported that ‘evidence for some superiority of the combinations over paracetamol was obtained, but the effects were weak and probably not clinically significant.’ It might be an alternative strategy in such situations to use (lower) doses, which combined produce the same level of analgesia elicited by each component, but with fewer adverse effects. This example also highlights again the importance of establishing, by rigorous preclinical and clinical evaluation, whether the combination is additive or synergistic, the optimal dose ratio and the adverse effect profile of the combination compared to the individual constituents.

Tramadol offers potential advantages over traditional opioids in combination therapy because its unique mechanism contributes to its favourable chronic safety profile, particularly with respect to respiratory depression, constipation, sedation, tolerance or dependence. Combining tramadol with acetaminophen provides a good example of the potential benefits of combination therapy. Each component has a unique analgesic mechanism of action, and it has been demonstrated that adding acetaminophen to tramadol results in synergistic analgesia in animals (51). It has been further demonstrated in humans that the combination is more effective and has a faster onset and longer duration of action than either component alone, without increasing the incidence of adverse events (59). Adding certain NSAIDs to tramadol may also result in synergistic antinociception. Tramadol use was shown to reduce NSAID (naproxen) doses in patients with osteoarthritis (68), and the combination of tramadol and flurbiprofen was shown to be more effective than either agent alone for pain following dental surgery (60). No tramadol/NSAID combinations are commercially available, but additional studies of such combinations (particularly with COX-2 NSAIDs) are needed.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANALGESIC CLASSES
  5. COMBINATION ANALGESICS
  6. CONCLUSIONS
  7. References

Many combination analgesics are available and are commonly prescribed for pain. The goal is to facilitate patient compliance, simplify prescribing and improve efficacy without increasing adverse effects. Clinical trials have recently begun to document the efficacy and tolerability of combination analgesics, but additional study of these and other combinations (such as acetaminophen or a NSAID with an opioid or tramadol) are clearly needed. In special cases, the combination of drugs from different analgesic classes results in synergistic analgesia, but not synergistic adverse effects, enabling the patient to achieve increased pain control or comparable control with a lower risk for adverse events.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANALGESIC CLASSES
  5. COMBINATION ANALGESICS
  6. CONCLUSIONS
  7. References
  • 1
    American Geriatrics Society Panel on Chronic Pain in Older Persons. (1998) AGS clinical practice guidelines: the management of chronic pain in older persons. Journal of the American Geriatrics Society, 46 , 635651.
  • 2
    American Medical Directors Association. (1999) Chronic Pain Management in the Long-Term Care Setting. Clinical Practice Guideline. Baltimore, MD: American Medical Directors Association.
  • 3
    Besson JM. (1999) The neurobiology of pain. Lancet, 353 , 16101615.DOI: 10.1016/s0140-6736(99)01313-6
  • 4
    Schug SA, Zech D, Dorr U. (1990) Cancer pain management according to WHO analgesic guidelines. Journal of Pain and Symptom Management, 5 , 2732.
  • 5
    American Pain Society. (1999) Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. Glenview, IL: American Pain Society.
  • 6
    American College of Rheumatology Subcommittee on Osteoarthritis. (2000) Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis and Rheumatism, 43 , 19051915.
  • 7
    Matthew MT & Nance PW. (1999) Analgesics. Opioids, adjuvants, and others. Physical Medicine and Rehabilitation Clinics of North America, 10 , 255273.
  • 8
    McQuay H. (1999) Opioids in pain management. Lancet, 353 , 22292232.DOI: 10.1016/s0140-6736(99)03528-x
  • 9
    Ameer B & Greenblatt DJ. (1977) Acetaminophen. Annals of Internal Medicine, 87 , 202209.
  • 10
    Lee CR, McTavish D, Sorkin EM. (1993) Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs, 46 , 313340.
  • 11
    Brune K. (1988) The pharmacological profile of non-opioid (OTC) analgesics: aspirin, paracetamol (acetaminophen), ibuprofen, and phenazones. Agents and Actions Supplements, 25 , 919.
  • 12
    Aronson MD. (1997) Nonsteroidal anti-inflammatory drugs, traditional opioids, and tramadol: contrasting therapies for the treatment of chronic pain. Clinical Therapeutics, 19 , 420432.
  • 13
    McGoldrick MD & Bailie GR (1997) Nonnarcotic analgesics: prevalence and estimated economic impact of toxicities. Annals of Pharmacotherapy, 31 , 221227.
  • 14
    Vane JR. (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biology, 231 , 232235.
  • 15
    Yaksh TL & Malmberg AB. (1993) Spinal actions of NSAIDS in blocking spinally mediated hyperalgesia: the role of cyclooxygenase products. Agents and Actions Supplements, 41 , 89100.
  • 16
    Gardner GC & Simkin PA. (2000) Adverse effects of NSAIDs. P & T, 16 , 750755.
  • 17
    Venkat K, Brown MD, Barkin R. (1998) Nonsteroidal anti-inflammatory drugs and gastroduodenal injury. American Journal of Therapeutics, 5 , 263272.
  • 18
    Singh G & Ramey DR. (1998) NSAID induced gastrointestinal complications: the ARAMIS perspective – 1997. Journal of Rheumatology, 25 , 816.
  • 19
    Whelton A. (1999) Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. American Journal of Medicine, 106(Suppl. 5B),13S24S.
  • 20
    Lipsky PE, Brooks P, Crofford LJ, et al. (2000) Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes and disease. Archives of Internal Medicine, 160 , 913920.
  • 21
    Björkman R, Hallman KM, Hedner J, Hedner T, Henning M. (1994) Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P. Pain, 57 , 259264.
  • 22
    Hunskaar S, Fasmer OB, Hole K. (1985) Acetylsalicylic acid, paracetamol and morphine inhibit behavioral responses to intrathecally administered substance P or capsaicin. Life Sciences, 37 , 18351841.
  • 23
    Björkman R. (1995) Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paracetamol. Experimental studies in the rat. Acta Anaesthesiologica Scandinavica Supplementum, 39(Suppl. 103),144.
  • 24
    Muth-Selbach US, Tegeder I, Brune K, Geisslinger G. (1999) Acetaminophen inhibits spinal prostaglandin E2 release after peripheral noxious stimulation. Anesthesiology, 91 , 231239.
  • 25
    Pelissier T, Alloui A, Paeile C, Eschalier A. (1995) Evidence of a central antinociceptive effect of paracetamol involving spinal 5HT3 receptors. Neuroreport, 6 , 15461548.
  • 26
    Pelissier T, Alloui A, Caussade F, et al. (1996) Paracetamol exerts a spinal antinociceptive effect involving an indirect interaction with 5-hydroxytry- ptamine3 receptors: in vivo and in vitro evidence. Journal of Pharmacology and Experimental Therapeutics, 278 , 814.
  • 27
    Raffa RB & Codd EE. (1996) Lack of binding of acetaminophen to 5-HT receptor or uptake sites (or eleven other binding/uptake assays). Life Sciences, 59 , L37L40.
  • 28
    Raffa RB, Stone DJ, Tallarida RJ. (2000) Discovery of ‘self-synergistic’ spinal/supraspinal antinociception produced by acetaminophen (paracetamol). Journal of Pharmacology and Experimental Therapeutics, 295 , 291294.
  • 29
    Raffa RB, Stone DJ Jr, Tallarida RJ. (2001) Unexpected and pronounced antinociceptive synergy between spinal acetaminophen (paracetamol) and phentolamine. European Journal of Pharmacology, 412 , R1R2.DOI: 10.1016/s0014-2999(01)00722-1
  • 30
    Schueler L & Harper JL. (1995) Acetaminophen toxicity: report of case and review of the literature. Journal of Oral and Maxillofacial Surgery, 53 , 12081212.
  • 31
    Maddrey WC. (1987) Hepatic effects of acetaminophen: enhanced toxicity in alcoholics. Journal of Clinical Gastroenterology, 9 , 180185.
  • 32
    Jaffe JH & Martin WR. (1985) Opioid analgesics and antagonists. In: Goodman LS, Gilman A, eds. The Pharmacological Basis of Therapeutics. New York: Macmillan, 491–581.
  • 33
    Benedetti C & Butler SH. (1990) Systemic analgesics. In: Bonica K, Loeser JD, Chapman CR, Fordyce WE, eds. The Management of Pain. Philadelphia: Lea & Febiger, 1640–1675.
  • 34
    Hammack JE & Loprinzi CL. (1994) Use of orally administered opioids for cancer-related pain. Mayo Clinic Proceedings, 69 , 384390.
  • 35
    Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL. (1992) Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. Journal of Pharmacology and Experimental Therapeutics, 260 , 275285.
  • 36
    Desmeules JA, Piguet V, Collart L, Dayer P. (1996) Contribution of monoaminergic modulation to the analgesic effect of tramadol. British Journal of Clinical Pharmacology, 41 , 712.
  • 37
    Raffa RB, Friderichs E, Reimann W, et al. (1993) Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol. Journal of Pharmacology and Experimental Therapeutics, 267 , 331340.
  • 38
    Halfpenny DM, Callado LF, Stamford JA. (1999) Is tramadol an antidepressant? British Journal of Anaesthesia, 82 , 480481.
  • 39
    Cicero TJ, Adams EH, Geller A, et al. (1999) A postmarketing surveillance program to monitor Ultram® (tramadol hydrochloride) abuse in the United States. Drug and Alcohol Dependence, 57 , 722.DOI: 10.1016/s0376-8716(99)00041-1
  • 40
    Russell IJ, Kamin M, Bennett RM, Schnitzer TJ, Green JA, Katz WA. (2000) Efficacy of tramadol in treatment of pain in fibromyalgia. Journal of Clinical Rheumatology, 6 , 250257.
  • 41
    Harati Y, Gooch C, Swenson M, et al. (1998) Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology, 50 , 18421846.
  • 42
    Tarradell R, Pol O, Farre M, Barrera E, Puig MM. (1996) Respiratory and analgesic effects of meperidine and tramadol in patients undergoing orthopedic surgery. Methods and Findings in Experimental and Clinical Pharmacology, 18 , 211218.
  • 43
    Moore PA, Crout RJ, Jackson DL, Schneider LG, Graves RW, Bakos L. (1998) Tramadol hydrochloride: analgesic efficacy compared with codeine, aspirin with codeine, and placebo after dental extraction. Journal of Clinical Pharmacology, 38 , 554560.
  • 44
    Fleischmann RM, Caldwell JR, Roth SH, Tesser JRP, Olson W, Kamin M. (2001) Tramadol for the treatment of joint pain associated with osteoarthritis: a randomized, double-blind, placebo-controlled trial. Current Therapeutic Research, 62 , 113128.DOI: 10.1016/s0011-393x(01)80021-7
  • 45
    Schnitzer TJ, Gray WL, Paster RZ, Kamin M. (2000) Efficacy of tramadol in treatment of chronic low back pain. Journal of Rheumatology, 27 , 772778.
  • 46
    Onghena P & Van Houdenhove B. (1992) Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain, 49 , 205219.
  • 47
    McQuay HJ, Tramèr M, Nye BA, Carroll D, Wiffen PJ, Moore RA. (1996) A systematic review of antidepressants in neuropathic pain. Pain, 68 , 217227.DOI: 10.1016/s0304-3959(96)03140-5
  • 48
    Backonja M, Beydoun A, Edwards KR, et al. (1998) Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus. A randomized controlled trial. JAMA, 280 , 18311836.
  • 49
    Van Elstraete AC, Pastureau F, Lebrun T, Mehdaoui H. (2000) Caudal clonidine for postoperative analgesia in adults. British Journal of Anaesthesia, 84 , 401402.
  • 50
    Joshi W, Reuben SS, Kilaru PR, Sklar J, Maciolek H. (2000) Postoperative analgesia for outpatient arthroscopic knee surgery with intraarticular clonidine and/or morphine. Anesthesia and Analgesia, 90 , 11021106.
  • 51
    Tallarida RJ & Raffa RB. (1996) Testing for synergism over a range of fixed ratio drug combinations: replacing the isobologram. Life Sciences, 58 , PL23PL28.DOI: 10.1016/0024-3205(95)02271-6
  • 52
    Ossipov MH, Harris S, Lloyd P, Messineo E, Lin BS, Bagley J. (1990) Antinociceptive interaction between opioids and medetomidine: systemic additivity and spinal synergy. Anesthesiology, 73 , 12271235.
  • 53
    Palangio M, Damask MJ, Morris E, et al. (2000) Combination hydrocodone and ibuprofen versus combination codeine and acetaminophen for the treatment of chronic pain. Clinical Therapeutics, 22 , 879892.DOI: 10.1016/s0149-2918(00)80060-0
  • 54
    Cooper SA, Engel J, Ladov M, Precheur H, Rosenheck A, Rauch D. (1982) Analgesic efficacy of an ibuprofen-codeine combination. Pharmacotherapy, 2 , 162167.
  • 55
    Cooper SA, Precheur H, Rauch D, Rosenheck A, Ladov M, Engel J. (1980) Evaluation of oxycodone and acetaminophen in treatment of postoperative dental pain. Oral Surgery, Oral Medicine, and Oral Pathology, 50 , 496501.
  • 56
    Dionne RA. (1999) Additive analgesic effects of oxycodone and ibuprofen in the oral surgery model. American Journal of Oral and Maxillofacial Surgeons, 57 , 673678.
  • 57
    Forbes JA, Bates JA, Edquist IA, et al. (1994) Evaluation of two opioid-acetaminophen combinations and placebo in postoperative oral surgery pain. Pharmacotherapy, 14 , 139146.
  • 58
    Wideman GL, Keffer M, Morris E, Doyle RT Jr, Jiang JG, Beaver WT. (1999) Analgesic efficacy of a combination of hydrocodone with ibuprofen in postoperative pain. Clinical Pharmacology and Therapeutics, 65 , 6676.
  • 59
    Medve R, Wang J, Karim R. (2001) Tramadol and acetaminophen tablets for dental pain. Anesthesia Progress, 48 , in press.
  • 60
    Doroschak AM, Bowles WR, Hargreaves KM. (1999) Evaluation of the combination of flurbiprofen and tramadol for management of endodontic pain. Journal of Endodontics, 25 , 660663.
  • 61
    Breivik EK, Barkvoll P, Skovlund E. (1999) Combining diclofenac with acetaminophen or acetaminophen-codeine after oral surgery: a randomized, double-blind single-dose study. Clinical Pharmacology and Therapeutics, 66 , 625635.
  • 62
    Mayoral CE, Marino RV, Rosenfeld W, Greensher J. (2000) Alternating antipyretics: is this an alternative? Pediatrics, 105 , 10091012.
  • 63
    Sunshine A, Olsen NZ, O'Neill E, Ramos I, Doyle R. (1997) Analgesic efficacy of a hydrocodone with ibuprofen combination compared with ibuprofen alone for the treatment of acute postoperative pain. Journal of Clinical Pharmacology, 37 , 908915.
  • 64
    Heidrich G, Slavic-Svircev V, Kaiko RF. (1985) Efficacy and quality of ibuprofen and acetaminophen plus codeine analgesia. Pain, 22 , 385397.
  • 65
    Caldwell JR, Hale ME, Boyd RE, et al. (1999) Treatment of osteoarthritis pain with controlled release oxycodone or fixed combination oxycodone plus acetaminophen added to nonsteroidal antiinflammatory drugs: a double blind, randomized, multicenter, placebo controlled trial. Journal of Rheumatology, 26 , 862869.
  • 66
    IMS Health. (1999) The top 200 prescriptions for by number of US prescriptions dispensed. www.rxlistcom/top200htm2001.
  • 67
    Zhang WY & Li Wan Po A. (1996) Analgesic efficacy of paracetamol and its combination with codeine and caffeine in surgical pain – a meta-analysis. Journal of Clinical Pharmacy and Therapeutics, 21 , 261282.
  • 68
    Schnitzer TJ, Kamin M, Olson WH. (1999) Tramadol allows reduction of naproxen dose among patients with naproxen-responsive osteoarthritis pain: a randomized, double-blind, placebo-controlled study. Arthritis and Rheumatism, 42 , 13701377.