Letters to the Editor
Tramadol for Acute Pain: A Review of the Evidence
to the editor: Kudos to Dr. Sachs for her attempt to develop an evidence-based approach to the use of oral analgesics for acute pain.1 However, her recommendation against the use of tramadol (Ultram) seems to be the result of selective reporting of the research literature, based on a randomized trial2 comparing tramadol with hydrocodone (Vicodin) and a randomized trial3 comparing tramadol with placebo or acetaminophen and codeine. Dr. Sachs does not cite a double-blind randomized trial4 of 200 adults that showed that tramadol (75 mg) plus acetaminophen was as effective as hydrocodone (10 mg) plus acetaminophen in relieving pain caused by extraction of impacted molars, and was less likely to cause adverse drug events. She also did not cite a meta-analysis5 of individual patient data that showed that, compared with placebo, tramadol (75 mg) plus acetaminophen had a number needed to treat (NNT) of 2.6 to reduce pain by 50 percent, which was comparable to the NNT of 2.4 for 5 mg of oxycodone (Oxycontin) plus acetaminophen in a separate meta-analysis.6 However, the meta-analysis5 of tramadol should be viewed cautiously because it is based on unpublished pharmaceutical company data.
Using a MEDLINE search strategy (tramadol and postoperative pain/drug therapy) limited to randomized controlled trials, I identified 104 separate trials comparing tramadol with a variety of other medications for the treatment or prevention of postoperative pain. The evidence from those trials is mixed, with some trials showing substantial benefit and others showing little benefit for tramadol.
I believe the evidence on tramadol for acute pain is mixed. It would be useful to have a trial comparing multiple doses of tramadol plus acetaminophen with multiple doses of hydrocodone plus acetaminophen. Until that time, it is prudent to keep tramadol plus acetaminophen as a therapeutic option for treating patients with acute pain. It appears to have at least moderate pain-relieving effects and may have fewer side effects than narcotic analgesics.
REFERENCES
1. Sachs CJ. Oral analgesics for acute nonspecific pain. Am Fam Physician 2005;71:913-8.
2. Turturro MA, Paris PM, Larkin GL. Tramadol versus hydrocodone-acetaminophen in acute musculoskeletal pain: a randomized, double-blind clinical trial. Ann Emerg Med 1998;32:139-43.
3. Stubhaug A, Grimstad J, Breivik H. Lack of analgesic effects of 50 and 100 mg oral tramadol after orthopaedic surgery: a randomized, double-blind, placebo and standard active drug comparison. Pain 1995;62:111-8.
4. Fricke JR Jr, Karim R, Jordan D, Rosenthal N. A double-blind, single-dose comparison of the analgesic efficacy of tramadol/acetaminophen combination tablets, hydrocodone/acetaminophen combination tablets, and placebo after oral surgery. Clin Ther 2002;24:953-68.
5. Edwards JE, McQuay HJ, Moore RA. Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain. J Pain Symptom Manage 2002;23:121-30.
6. Edwards JE, Moore RA, McQuay HJ. Single dose oxycodone and oxycodone plus paracetamol (acetaminophen) for acute postoperative pain. Cochrane Database Syst Rev 2000;(2):CD002763.
in reply: I thank Dr. Sonis for the opportunity to further discuss important caveats that govern the interpretation of studies about analgesic efficacy. As Dr. Sonis states, our review1 cited only a sample of the literature pertaining to tramadol (Ultram). This series in American Family Physician aims to provide "succinct, evidence-based, authoritative clinical reviews"2 rather than an exhaustive review of every related paper that is published. In addition to analgesic efficacy, our literature selection pays careful attention to appropriateness of comparison medication, adverse effects, and research sponsor motivation. Based on these guidelines, I believe that quality studies with appropriate comparison groups do not support the use of tramadol in the initial treatment of acute pain.
Dr. Sonis cites two specific studies3,4 supporting the efficacy of a combination of tramadol and acetaminophen (Ultracet). Rather than equality, the first study3 actually showed greater efficacy in time to pain relief and time to remedication for a combination of hydrocodone and acetaminophen when compared with the combination of tramadol and acetaminophen. Additionally, two of the four study authors3 were employed by the makers of Ultracet.
The second cited article4 is a Cochrane review of the combination of tramadol and acetaminophen versus acetaminophen alone or ibuprofen.4 This review reports efficacy of the combination in some studies but not in others. With the addition of acetaminophen, tramadol demonstrated superior analgesia to acetaminophen alone, but in no study was it superior to 400 mg of ibuprofen, and in several studies it was inferior. Furthermore, in the five studies that used a dose of 975 mg
of acetaminophen as a comparison, the investigators failed to demonstrate superiority of the tramadol combination over acetaminophen alone.
The Cochrane review also reported significantly more side effects with tramadol than with the recommended first-line analgesics. For single-dose oral tramadol (75 mg) plus acetaminophen (650 mg), the number needed to treat to harm for a patient to report any adverse effect was 5.4 (4.0 to
8.2). Neither acetaminophen (650 mg) nor ibuprofen (400 mg) demonstrated any increase in adverse effects compared with placebo (relative risk: 0.9 [0.7 to 1.3] and 0.7 [0.5 to 1.01], respectively). For dental pain patients, this review4 reported vomiting in one out of every six patients receiving tramadol.
In summary, the literature fails to demonstrate increased efficacy of the combination of tramadol and acetaminophen over other recommended first-line analgesics (i.e., ibuprofen [400 mg] or acetaminophen [1,000 mg]) but does demonstrate a striking increase in adverse events.
REFERENCES
1. Sachs CJ. Oral analgesics for acute nonspecific pain. Am Fam Physician 2005;71:913-8.
2. American Family Physician. Authors guide. Accessed online, July 5, 2005, at: http://www.aafp.org/x13554.xml.
3. Fricke JR Jr, Karim R, Jordan D, Rosenthal N. A double-blind, single-dose comparison of the analgesic efficacy of tramadol/acetaminophen combination tablets, hydrocodone/acetaminophen combination tablets, and placebo after oral surgery. Clin Ther 2002;24:953-68.
4. Edwards JE, McQuay HJ, Moore RA. Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain. J Pain Symptom Manage 2002;23:121-30.
Encounter Form for Patients with Acute Knee Injuries
to the editor: Thank you for the "Point-of-Care Guide"1 in the March 15, 2005, issue of American Family Physician. I have several comments that I hope are helpful:
Although the pivot shift maneuver is probably the most accurate physical examination for detecting a torn anterior cruciate ligament (ACL) in the chronic setting,2 it is not likely to be very useful acutely. Patients with an acutely torn ACL usually have a significant hemarthrosis with associated guarding and decreased range of motion. These factors make the pivot shift maneuver difficult to perform (and uncomfortable for the patient) in the acute setting.3 Clearly, the Lachman maneuver is a more appropriate test for ACL integrity acutely.
The likelihood ratios and predictive values used in the encounter form1 are derived from only one study.4 They seem at odds with my clinical experience and also with the results of a prior meta-analysis.2 The study4 by Jackson and colleagues discounted patient history as a way of determining pretest probability, and instead relied on estimated prevalence of the particular injuries in the population. Although the evidence-based literature has not proven the utility of the history in diagnosing acute knee injuries, I believe history is the key to accurate diagnosis. For example, in the case mentioned in the article1 regarding the author's knee injury, the most obvious diagnosis, based on history alone, was clearly a torn (most likely, a bucket-handle tear) meniscus with intermittent locking caused by displacement of the flap. The physical examination did not appear to contribute much to the diagnosis, although the presence of a small effusion would be consistent with a meniscal tear.
Joint line tenderness has been found to be the most sensitive indicator of a meniscal tear, although it has poor specificity.2,5,6 McMurray's maneuver has been found to have a relatively low sensitivity, with varying specificity,2,6 and also is extremely difficult to perform in the setting of an acute knee injury. If the patient is in pain, has a significant effusion, has decreased range of motion, or is guarding, the maneuver cannot be performed accurately. Further, it will be painful for the patient, and may prevent the patient from relaxing for any other part of the examination. Various modifications (e.g., Apley's) may be used in this setting but also have been found to have relatively poor accuracy.2,6 Newer maneuvers, such as the Thessaly test, may be useful and merit further evaluation.
The patient encounter form1 is very concise. However, a primary care physician who uses this form and does not have a good musculoskeletal medicine background may miss or not even consider other important knee injuries, including damage to the posterior cruciate ligament, collateral ligaments, posterolateral corner, and patellofemoral joint. Also, the form does not prompt the user to evaluate or record range-of-motion, strength, or neurovascular deficits. No form is perfect, but perhaps adding a few items in this case might be worthwhile.
REFERENCES
1. Ebell MH. Evaluating the patient with a knee injury (point-of-care guides). Am Fam Physician 2005;71:1169-72.
2. Solomon DH, Simel DL, Bates DW, Katz JN, Schaffer JL. The rational clinical examination. Does this patient have a torn meniscus or ligament of the knee? Value of the physical examination. JAMA 2001;286:1610-20.
3. Brown JR, Trojian TH. Anterior and posterior cruciate ligament injuries. Prim Care 2004;31:925-56.
4. Jackson JL, O'Malley PG, Kroenke K. Evaluation of acute knee pain in primary care. Ann Intern Med 2003;139:575-88.
5. Eren OT. Arthroscopy. The accuracy of joint line tenderness by physical examination in the diagnosis of meniscal tears. Arthroscopy 2003;19:850-4.
6. Malanga GA, Andrus S, Nadler SF, McLean J. Physical examination of the knee: a review of the original test description and scientific validity of common orthopedic tests. Arch Phys Med Rehabil 2003;84:592-603.
in reply: I would like to thank Dr. Cohen for his thoughtful comments regarding the encounter form for acute knee injury.1 I agree with his comments about the pivot shift and McMurray tests, which may be difficult to perform in patients who have a great deal of pain and swelling. Although the form does state "Recheck in ___ days," it would be more clear to add an item reading "Examination limited; reexamine in ___ days," to the Assessment/Plan portion of the encounter form. I also have added prompts reminding users to evaluate the patient's strength, range of motion, and neurovascular status. This revised version of the encounter form is available online at http://www.aafp.org/afp/20050315/pocform.html.
The data regarding the accuracy of individual elements of the knee examination were based largely on the meta-analysis by Jackson and colleagues published in 2003.2 This study agrees with Dr. Cohen's comment that joint line tenderness is sensitive but not specific, and that the opposite holds true for the McMurray test. Dr. Cohen cites a study3 performed by a single physician in Turkey on Turkish military recruits 18 to 20 years of age. The author3 found a very good sensitivity and specificity of this finding for lateral meniscal tears, which was better than had been reported previously in the literature. Because this study3 is only one unblinded study based on the physical examination of one examiner, it is of a lower level of evidence than the well-done meta-analysis by Jackson.2
Regarding the differences between the results of Jackson's 2003 meta-analysis2 and Solomon's 2001 meta-analysis,4 in some cases they are small and clinically unimportant. For example, the positive and negative likelihood ratios for joint line tenderness were
1.1 and 0.8, respectively, in Jackson; and 0.9 and 1.1 in Solomon. When they differ, as with the McMurray test, which Jackson found to be more accurate than did Solomon, it may be because Jackson's article identified an additional study. Ultimately, I chose to rely on data from the Jackson
meta-analysis because it was more recent and used what I thought were the more rigorous methods.
Finally, I did not intend to minimize the role of the history, and did include several key findings as "checkoffs." Unfortunately, existing studies5,6 have not shown that the clinical history is highly accurate for distinguishing between different kinds of knee injury. However, these studies5,6 are limited in number and quality. I think there is a great deal more work to be done in developing more rational strategies for evaluating patients with acute knee injury.
REFERENCES
1. Ebell MH. Evaluating the patient with a knee injury (point-of-care guides). Am Fam Physician 2005;71:1169-72.
2. Jackson JL, O'Malley PG, Kroenke K. Evaluation of acute knee pain in primary care. Ann Intern Med 2003;139:575-88.
3. Eren OT. Arthroscopy. The accuracy of joint line tenderness by physical examination in the diagnosis of meniscal tears. Arthroscopy 2003;19:850-4.
4. Solomon DH, Simel DL, Bates DW, Katz JN, Schaffer JL. The rational clinical examination. Does this patient have a torn meniscus or ligament of the knee? Value of the physical examination. JAMA 2001;286:1610-20.
5. Boeree NR, Ackroyd CE. Assessment of the menisci and cruciate ligaments: an audit of clinical practice. Injury 1991;22:291-4.
6. Miller GK. A prospective study comparing the accuracy of the clinical diagnosis of meniscus tear with magnetic resonance imaging and its effect on clinical outcome. Arthroscopy 1996;12:406-13.
Case Report: Expanding the Differential Diagnosis of Intractable Cough
to the editor: We present a patient with an unusual cause for persistent debilitating cough, which adds to the myriad differential diagnoses of chronic cough.
A 43-year-old male factory worker presented with a four-month history of persistent, dry, debilitating cough (exacerbated by perfumes and other strong odors) and progressive hoarseness. The cough was so frequent and severe that he was forced to stop working. He also complained of episodic "heartburn." He had a 10 pack-year history of smoking but had stopped four years previously. He did not use alcohol. His allergies to house dust and dog dander were treated with antihistamines, and he had no history of asthma. A tympanomastoidectomy had been performed 14 years previously for chronic otitis media. A ventilating tube was inserted into the left tympanic membrane four months before presentation in our office. He had received treatment from a pulmonologist with inhaled and oral corticosteroids, neither of which provided relief. Pulmonary function tests, chest radiograph, computed tomography of the lungs and sinuses, and bronchoscopy with washings were negative. Despite a negative pH probe study, he was started on omeprazole (Prilosec) for presumed gastroesophageal reflux.
During examination in our otolaryngology office, the patient had a dry, nonproductive, hacking cough. His nose, pharynx, and larynx were normal. Examination of the left ear identified a plastic pressure equalization ventilation tube deep (medial) in the external auditory canal.
On a follow-up visit three weeks later, he stated that his cough had ceased completely one week previously. The clinical examination was again unremarkable, except that the pressure equalization tube was now positioned laterally in the external auditory canal and was removed easily. On further questioning, he recalled that his cough began immediately after placement of the tube.
We concluded that his intractable cough was caused by the ventilation tube either through or on the surface of the tympanic membrane, presumably with persistent stimulation of a branch of the vagus nerve.
Ventilation tubes have been placed through the tympanic membrane since the 1950s for aeration of the diseased middle ear. Tens of millions of tympanostomy tubes have been placed worldwide in children and adults, without cough being a frequently associated complication. We found only one reported case of a ventilating tube causing similar symptoms.1
The sensory nerve supply of the epithelium of the external auditory canal is via branches of the trigeminal, facial, glossopharyngeal, and vagus nerves. Arnold's nerve is the auricular branch of the vagus nerve that innervates the deep external auditory canal and courses over the medial wall of the middle ear (the promontory). Stimulation of Arnold's nerve incites the cough reflex that sometimes occurs with manipulation of the medial external auditory canal.2 Why the presence of ventilating tubes through the tympanic membrane does not cause coughing in the majority of patients remains a mystery.
This case demonstrates that in patients with recalcitrant cough unresponsive to appropriate treatment, otoscopic examination and removal of any foreign material from the external auditory canal is worth trying before more invasive investigations are conducted.
REFERENCES
1. Feldman JI, Woodworth WF. Cause for intractable chronic cough: Arnold's nerve. Arch Otolaryngol Head Neck Surg 1993;119:1042.
2. Hollinshead WH. Anatomy for surgeons: the head and neck. 3d ed. Philadelphia: Harper & Row, 1982.
The article "Lymphogranuloma Venereum Among Men Who Have Sex with Men" ("Practice Guideline Brief," March 15, 2005, page 1222) incorrectly listed the recommended dosage of doxycycline as 10 mg rather than 100 mg. In the first paragraph under the treatment heading on page 1225, the first sentence should read: "The recommended treatment is administration of 100 mg of doxycycline, twice daily for 21 days." The online version of this article has been corrected.
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