Original Research | Published:

A three-part study to investigate the incidence and potential etiologies of tadalafil-associated back pain or myalgia

International Journal of Impotence Research volume 17, pages 455461 (2005) | Download Citation

Subjects

Abstract

The potential mechanisms underlying back pain and/or myalgia experienced by men taking tadalafil were investigated. An integrated analysis of 10 placebo-controlled tadalafil clinical trials (N=1846) showed that the incidence of back pain and/or myalgia was 9.4% in patients receiving tadalafil 10 mg (N=394), 8.3% in patients receiving tadalafil 20 mg (N=883) and 3.7% in placebo-treated patients (N=569). One (0.3%) patient receiving tadalafil 10 mg, six (0.7%) patients receiving tadalafil 20 mg, and no patients receiving placebo discontinued treatment due to back pain and/or myalgia. In a prospective study in healthy volunteers, no substantial changes were observed in laboratory markers indicative of inflammation or muscle damage, and tadalafil did not affect renal plasma flow nor produce lumbar or gluteal myositis by positron emission tomography scan or magnetic resonance imaging. Although the mechanism of back pain and/or myalgia remains unknown, these events appear to be self-limiting and a general effect of phosphodiesterase 5 inhibition.

Introduction

Oral phosphodiesterase 5 (PDE5) inhibitors are now standard therapeutic options for the treatment of erectile dysfunction (ED). All three currently marketed PDE5 inhibitors sildenafil citrate (sildenafil), tadalafil, and vardenafil hydrochloride (vardenafil), are effective and generally well tolerated.1, 2, 3, 4, 5, 6, 7 The most common side effects of this class of medications include headache, flushing, dyspepsia, and rhinorrhea, the majority of which may be related to the mild vasodilatory effects associated with PDE5 inhibition.8, 9 Back pain or myalgia have also been reported to varying degrees with each of the three marketed PDE5 inhibitors.4, 10, 11, 12

In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12–24 h after dosing and typically resolved within 48 h. The back pain and myalgia associated with tadalafil treatment was characterized by diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort, and was exacerbated by recumbency. In general, pain was reported as mild or moderate in severity, and resolved with acetaminophen or nonsteroidal anti-inflammatory drugs when necessary. Severe back pain was reported infrequently (<5% of all reports). Overall, approximately 0.4% of all tadalafil-treated ED patients discontinued treatment as a consequence of back pain or myalgia, within the same range as discontinuations for headache (0.8%).4

The origins of lumbar pain in general may be complex, myriad, and include structural, degenerative, and inflammatory processes of the spine, as well as pain referred from the abdomen, pelvis, and urinary tract.13, 14 HMG-CoA reductase inhibitors have been reported to induce clinically important myositis or rhabdomyolysis, which may present with back pain or myalgia.15

To investigate the nature of back pain associated with tadalafil use, we first conducted a retrospective analysis of the combined incidence of eight adverse event terms coded in the databases from 10 placebo-controlled studies of tadalafil for ED and possibly associated with back pain and/or myalgia. In the second part of the investigation, we prospectively conducted a clinical pharmacology study in healthy volunteers using three radiologic examinations ([18F]-fluorodeoxyglucose positron emission tomography scan ([18F]-FDG-PET),16 gadolinium-enhanced magnetic resonance imaging (MRI) scans,17 and technetium mertiatide (Tc99m) scanning) to investigate whether there is a pathological process or venocongestion localized in the lumbar and gluteal muscles, or an underlying abnormality in renal plasma flow. In the final part, we conducted a prospective laboratory investigation to examine the possible involvement of inflammatory or myolytic processes in the reports of back pain and/or myalgia.

The results of this investigation indicated that back pain or myalgia induced by tadalafil occurs with a combined incidence of approximately 9% in patients with ED, and are not associated with a serious underlying pathology.

Patients and methods

Part 1: Integrated data analysis

We retrospectively analyzed a large database of patients with ED who had enrolled in one of 10 multicenter, randomized, placebo-controlled, double-blind, efficacy, and safety studies conducted between November 1999 and September 2002. Nine of the 10 studies were included in the integrated analysis of 11 tadalafil studies previously reported.18 The remaining study reported here enrolled men with diabetes mellitus and ED.19 Inclusion and exclusion criteria, study design, and patient demographics have been described previously.18, 19 Briefly, men ≥18 y old with a ≥3-month history of ED were randomized to 12 weeks of treatment with placebo or tadalafil taken as needed up to once per day. Symptoms reported by patients during the clinical trials were recorded verbatim, then classified using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Eight terms including back pain, myalgia, back stiffness, buttock pain, coccydynia, loin pain, pain NOS (not otherwise specified), and sacral pain were collectively referred to as ‘back pain and/or myalgia.’ New or worsened reports of back pain and/or myalgia reports during the study period were summarized for all randomized patients treated with placebo or tadalafil 10 or 20 mg. When a patient reported more than one event, only the most severe event was counted. Patient discontinuation rates due to back pain and/or myalgia were summarized descriptively.

Part 2: PET, MRI, and radionuclide testing

Healthy males, 18–45 y of age, were enrolled into a double-blind, two-period crossover study comparing a single dose of either placebo and tadalafil 20 mg or placebo and tadalafil 80 mg. The periods were separated by a 10-day washout period. Subjects were resident in a Clinical Pharmacology Unit the night before dosing and through 24–30 h post-dose. At 22–30 h after dosing in each period, radionuclide renal scan, bilateral gadolinium-enhanced MRI scans of the lumbar and gluteal muscles, and [18F]-FDG-PET scans were performed.20, 21 The timing of these assessments corresponded to the time of peak incidence of reported back pain and/or myalgia following tadalafil dosing in subjects enrolled in clinical pharmacology studies (12–24 h post dose).10 Effective renal plasma flow in each kidney (ml/min/1.73 m2) was assessed by determining Tc99m clearance.22 Subjects returned approximately 48 h post-dose for clinical laboratory evaluations and physical examination.

The outcome measures for the MRI scan were qualitative comparisons for the presence of fasciitis, vasculitis, myositis, abscess and lumbar and gluteal muscle venocongestion after dosing, relative to the predose assessment. The outcome measure for FDG PET was the standardized uptake value (SUV) of radiolabeled glucose. The outcome measure for the 99mTc mertiatide study was effective renal plasma flow. All assessments were made by two treatment-blinded qualified radiologists or nuclear medicine physicians.

All subjects who completed at least one study period were included in the analysis. An analysis of covariance (ANCOVA) model that included terms for baseline, subject, period, and treatment was used to calculate the least-squares means and residual variance to compute 95% confidence intervals for the post-baseline effective renal plasma flow and PET scan SUV. Categorical changes from baseline in MRI scan data were made (worse, better, or same). Values of the same or better were pooled together and McNemar's test performed to test for treatment differences. For blood flow data, values of −1 (decrease) and 0 (no change) were pooled together, and the McNemar's test performed to test for treatment differences.

Part 3: Tests for inflammatory conditions

All subjects enrolled in one of five double-blind, placebo-controlled, crossover-design, clinical pharmacology studies conducted between August and December 2002 were categorized as to whether they experienced a back pain and/or myalgia event with an onset of 0–48, >48 h after dosing, or not at all. These studies enrolled healthy 18–65 y-old men, men with diabetes, or men with controlled hypertension. Subjects received either a single dose of placebo or tadalafil 20, 40, or 80 mg, or placebo or tadalafil 20 mg daily for 6 days. All study subjects underwent laboratory evaluations (Table 1) at baseline and 24–48 h after placebo or tadalafil administration. Prior to receiving the study treatment, subjects were instructed to report any back pain and/or myalgia or muscle aches to the investigator. Subjects who developed back pain and/or myalgia during treatment were evaluated clinically and had directed physical examinations. If the back pain and/or myalgia occurred during the follow-up period (>48 h post dose), subjects were required to return to the study site within 48 h of symptom onset for examinations and evaluations as above, including laboratory tests (Table 1).

Table 1: Laboratory tests measured

Analysis of the overall treatment effect on the change of laboratory values from entry at each time point was performed using a ranked analysis of variance (ranked ANOVA) model that included the treatment group, adjusted for pooled site.

Results

Part 1: Integrated data analysis

The clinical study database comprised 1846 patients with ED, of whom 569 received placebo, 394 received tadalafil 10 mg, and 883 received tadalafil 20 mg. The placebo and tadalafil groups were well balanced for demographic and baseline disease characteristics. The mean age (±s.d.) of patients was 57.4±10.3 in the placebo group, 57.8±10.1 in the tadalafil 10 mg group, and 57.0±10.5 in the tadalafil 20 mg group. Overall, 25.4% of patients were 65 y or older. The patients in these studies were Caucasian (76.9%), East or Southeast Asian (15.8%), African American (3.2%), Hispanic (3.1%), or other (0.9%). Patients’ ED had an organic (62.7%), psychogenic (10.5%), or mixed (organic/psychogenic (26.8%)) etiology. Major comorbidities included histories of hypertension (30.6%), diabetes mellitus (27.7%), or hyperlipidemia (17.8%).

The incidence of back pain and/or myalgia was 3.7% in placebo-treated patients, 9.4% in patients receiving tadalafil 10 mg, and 8.3% in patients receiving tadalafil 20 mg. Patients who discontinued treatment due to back pain and/or myalgia included one (0.3%) receiving tadalafil 10 mg, six (0.7%) receiving tadalafil 20 mg, and none receiving placebo.

Part 2: PET, MRI, and radionuclide testing

[18F]-FDG-PET was used to identify an inflammatory process in the region, as increased uptake of glucose is associated with an inflammatory process.16 Gadolinium-enhanced MRI scans were used to detect evidence of localized inflammation (eg, fasciitis, vasculitis, myositis, and abscess) and lumbar and gluteal venocongestion.17 Finally, renal plasma flow was assessed using a radionuclide scan following intravenous injection of Tc99m to primarily test the hypothesis that tadalafil induced renal artery vasodilatation, possibly leading to distension of the renal capsule and pain.

A total of 20 subjects were enrolled into this radiographic investigation, 10 each in the tadalafil 20 mg (Group 1) and 80 mg (Group 2) dose levels. In all, 17 subjects completed both treatment periods. One subject from Group 1 discontinued before randomization, one subject from Group 2 did not return for the post-dose imaging studies after receiving placebo during the first treatment period, and one subject from Group 2 received placebo during the first treatment period but did not return for the second treatment period. The mean ages (±s.d.) were 29±9.7 (N=9) in Group 1 and 26±7.1 (N=8) in Group 2. No subject discontinued due to an adverse event. Back pain and/or myalgia was reported by three subjects following tadalafil 20 mg administration, three subjects following tadalafil 80 mg administration and two subjects following placebo administration.

There were no clinically meaningful or significant differences between the mean effective renal plasma flow rates following tadalafil administration when compared with placebo (Table 2). None of the subjects had a change in tissue inflammation (fasciitis, vasculitis, myositis, or abscess) or blood flow in the lower lumbar or gluteal muscles as assessed by MRI at 24 h postdose compared to predose following any treatment (data not shown). No subject exhibited a change in distribution of renal perfusion and/or function that could be ascertained by visual inspection of the flow images during the initial phase of radiopharmaceutical distribution or during the renogram (renal uptake, excretion and clearance) component of the study. There were no significant differences in [18F]-FDG SUV for the right and left lumbar and gluteal muscles between tadalafil 20 mg and 80 mg and corresponding placebo treatments (Table 3). There were no subjects with an abnormal focal or diffuse localization of the FDG radiopharmaceutical agent.

Table 2: Mean effective renal plasma flow
Table 3: [18F]-FDG-PET mean SUV

Part 3: Tests for inflammatory conditions

A total of 283 subjects entered the five clinical pharmacology crossover studies. Of these, 273 subjects were exposed to placebo, and 195 subjects were exposed to 20 mg tadalafil, 60 to tadalafil 40 mg and eight to tadalafil 80 mg. Back pain and/or myalgia were reported by 26 and 146 subjects during placebo and tadalafil treatments, respectively. Of the total back pain and/or myalgia adverse events reported by tadalafil-treated subjects, 95.6% were mild or moderate in severity, with two (1.5%) leading to discontinuation from the study. Each subject experiencing back pain and/or myalgia was evaluated clinically, and their laboratory test results were reviewed by the investigator. No subject was deemed medically to have developed muscle damage or an inflammatory process accounting for the symptoms.

Laboratory data were collected for 273 (96.5%) during placebo treatment and 268 (94.7%) during tadalafil treatment. All of the laboratory parameters listed in Table 1 were analyzed. Five representative laboratory parameters potentially indicative of an inflammatory process or muscle damage are presented: creatine phosphokinase (CPK), C-reactive protein (CRP), leukocyte counts, erythrocyte sedimentation rate (ESR), and aldolase.23, 24 For each selected laboratory evaluation, mean values obtained at baseline and during pain (onset 0–48 or >48 h after dosing) were comparable (Figure 1). Mean changes from baseline between treatment groups for three of the five tests were not significantly different (all p>0.05). Leukocyte counts were lower 0–48 h post treatment in the tadalafil group experiencing back pain and/or myalgia compared with placebo (p=0.028), and the mean ESR in the tadalafil-treated subjects 0–48 h post-treatment was greater than that for placebo (p=0.04). The magnitudes of the differences between treatment groups for both parameters were small and not clinically meaningful. No tadalafil-treated subjects experiencing back pain and/or myalgia exhibited a CRP level (≥5 mg/dl) or ESR value suggestive of an inflammatory response (≥100 mm/h).23, 25 No tadalafil-treated subject had a post-dose absolute eosinophil count ≥1000 cells/μl, a level associated with eosinophilia–myalgia syndrome.26 No tadalafil-treated subject had a CPK or aldolase level in an abnormal range that may be indicative of myopathy or rhabdomyolysis.15, 27

Figure 1
Figure 1

Clinical laboratory parameters. Baseline and post-baseline measurements for subjects who developed back pain and/or myalgia during placebo (n=26) or tadalafil (n=146) treatment. (a) CPK, upper limit 198 U/l. (b) CRP, upper limit 0.287 mg/dl. (c) Leukocytes, normal range 3.8–10.7 × 109/l. (d) ESR, upper limit 16 mm/h. (e) Aldolase, normal range 1.2–7.6 U/l. Key: , mean; , median; and •, the maximum value for all subjects, if above bars; box, the 25–75% range; bars, the maximum subject value within 1.5 × of the interquartile range; mg/dl, milligrams per deciliter; mm/h, millimeters per hour; U/l, units per liter.

Laboratory parameters were also compared between all placebo-treatment periods and tadalafil-treatment periods, regardless of back pain and/or myalgia symptoms (N=541). This analysis did not indicate any clinically relevant differences between tadalafil and placebo for any parameter (data not shown). When a similar analysis was performed comparing tadalafil-treated subjects with back pain and/or myalgia to those that did not have these symptoms (N=268), no clinically relevant difference was found for any laboratory parameter (data not shown).

Comment

Part 1 of this article was a retrospective, integrated analysis of the tadalafil clinical trial database of 10 placebo-controlled efficacy and safety studies of tadalafil. This analysis showed that 8.3–9.4% of ED patients treated with tadalafil developed back pain and/or myalgia compared with 3.7% in placebo-treated patients, with <1% of patients discontinuing from studies because of these adverse events.

In part 2, radiologic studies with gadolinium-enhanced MRI and [18F]-FDG-PET in healthy volunteers showed that tadalafil treatment was not associated with changes indicative of an underlying inflammatory condition or muscle injury. The MRI scans also failed to show evidence for venocongestion in the lumbar or gluteal muscles following tadalafil treatment. These radiographic techniques may not be sufficiently sensitive to detect subtle changes in pooling of venous blood in the large muscle groups of the lower back and gluteal region, however. Renal radionuclide scans showed that effective renal plasma flow was unaffected by tadalafil treatment. No anatomic or functional abnormality was noted on renal scan. In order to increase the opportunity to observe tadalafil-related effects in the radiologic study, tadalafil was administered at the 80-mg dose, four times the maximum marketed dose. No diagnostic changes were seen even though participants in the radiologic study did develop back pain and/or myalgia consistent with the pattern of back pain and/or myalgia seen in other tadalafil clinical pharmacology studies. Thus, the lack of radiologic findings supports the conclusion that gross renal or muscular damage did not underlie the back pain and/or myalgia.

In Part 3, a prospective study of 268 tadalafil-treated subjects during clinical pharmacology studies showed that back pain and/or myalgia were not associated with laboratory evidence of inflammation, vasculitis, renal injury, or muscle injury. Specifically, normal BUN, serum creatine, serum potassium concentrations, and urinalyses argue against major renal parenchymal damage. Normal serum LDH, SGOT, and SGPT argue against infarction of kidney, liver, or muscle. Serum CPK and aldolase measurements indicate the absence of rhabdomyolysis. Finally, normal ESR, white blood cell counts, and serum CRP concentration indicate the absence of vasculitis.

It is notable that the incidence of back pain and/or myalgia was higher in clinical pharmacology studies than in the much longer, ambulatory ED patient clinical studies. There may be several reasons for the higher incidence reported in clinical pharmacology studies. (1) Subjects were housed in a Clinical Unit and restricted in their physical activities per protocol. Sitting and lying in the recumbent position may predispose to the development of back pain and/or myalgia.10 (2) Subjects participating in clinical pharmacology studies were typically younger than patients with ED, and it is possible that the younger age may be a risk factor for PDE5 inhibitor-associated back pain and/or myalgia. (3) Higher doses of tadalafil were administered than the maximum marketed dose of 20 mg. (4) As subjects were frequently asked about the occurrence of adverse events during their stay in the Clinical Unit, and specifically about back pain and/or myalgia, there may have been a reporting bias in the clinical pharmacologic studies.

Back pain and myalgia have been reported with other PDE5 inhibitors.11, 26, 28, 29, 30, 31, 32 For example, myalgia was reported in 7.4% of patients administered sildenafil 50 mg twice daily, and in 10% of patients administered sildenafil 50 mg thrice daily. Since back pain and myalgia adverse events are not unique to tadalafil, the mechanism is likely to be associated with PDE5 inhibition and unlikely to be related to tadalafil's modest inhibition of PDE11A. Tadalafil is 40-fold less inhibitory of PDE11A compared with PDE5 in vitro.33

These studies explored the potential serious causes for back pain and/or myalgia, including muscular trauma/damage, abscess, inflammatory processes, myositis, vasculitis, fasciitis, rhabdomyolysis, venocongestion, or kidney pathology.13, 14, 15 None of these serious mechanisms were supported by these results. Thus, the mechanism underlying this phenomenon remains unknown, but the symptoms are self-limited and we found no evidence of injury to the muscles or kidneys.

Conclusion

Back pain and/or myalgia events in tadalafil-treated subjects appear indistinguishable from idiopathic back pain and/or myalgia associated with placebo treatment using the measurements and laboratory tests employed in this study. Although the pathophysiological mechanisms leading to back pain and/or myalgia in association with tadalafil treatment remain unknown, these findings identify no serious underlying medical pathology. As these events are also associated with sildenafil and vardenafil, back pain and/or myalgia may be a class effect of PDE5 inhibition.

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Acknowledgements

Funding for this and the parent studies was provided by Lilly ICOS LLC. We wish to thank Chris Fischer of ICOS Corporation for his assistance in the preparation of the manuscript.

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Affiliations

  1. Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio, USA

    • A D Seftel
  2. University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

    • J Farber
  3. Division of Nuclear Medicine, Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana, USA

    • J Fletcher
  4. ICOS Corporation, Bothell, Washington, USA

    • M C Deeley
    •  & A Yu
  5. Lilly Research Laboratories, Indianapolis, Indiana, USA

    • A Elion-Mboussa
    •  & A Hoover
  6. University of Washington School of Medicine, Seattle, Washington, USA

    • P Fredlund

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Correspondence to A D Seftel.

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DOI

https://doi.org/10.1038/sj.ijir.3901374

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