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PAIN MEDICINE

Oral Doxepin Rinse: The Analgesic Effect and Duration of Pain Reduction in Patients with Oral Mucositis Due to Cancer Therapy

Joel B. Epstein, DMD, MSD^*, Joshua D. Epstein, MA, Matthew S. Epstein, BS, Hal Oien, DDS, and Edmond L. Truelove, DDS, MSD^¶

From the *Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, and Chicago Cancer Center, College of Medicine, University of Illinois, Chicago, Illinois; Department of Pharmaceutical Economics and Policy, University of Southern California, Los Angeles, California; Fred Hutchinson Cancer Research Center, Seattle; Private General Dental Practice, Beaverton, Oregon; and ¶Department of Oral Medicine, University of Washington, Seattle, Washington.

Address correspondence and reprint requests to J. Epstein, DMD, Department of Oral Medicine, 801 South Paulina, Chicago, Ill 60612. Address e-mail to jepstein{at}uic.edu.

	Abstract

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This research expands on our prior study, in which we assessed pain reduction after topical doxepin rinse in patients with oral mucositis resulting from cancer and cancer therapy. We continued to enroll patients with painful oral mucositis attributable solely to cancer therapy and performed further analysis on the duration of pain reduction. Fifty-one patients with oral mucositis were enrolled. Mucositis was scored and oral pain was assessed with a visual analog scale before doxepin oral rinse (5 mg/mL) and at regular intervals up to 4 h after rinsing. Of those who reported pain reduction, 95% did so within 15 min of rinsing with doxepin. In the total sample, the average patient reported a 70% maximum decrease in pain (P < 0.0001). Recurrence of pain was slow and at the conclusion of the study 19 patients (37%) still reported a reduction from baseline pain. With this censored data we used Cox-proportional hazards to determine what variables best explained longer duration of pain reduction. Our final model determined that more severe baseline pain, worse mucosal erythema score, or a larger relative maximum reduction in pain were all associated with a slower rate of pain recurrence after oral rinsing (all P < 0.01).

	Introduction

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Oral mucositis is a common complication of cancer therapy after head and neck radiation therapy, aggressive chemotherapy that may cause neutropenia, and hematopoietic cell transplantation (HCT) (1). Oral mucositis negatively impacts quality of life and is the most debilitating complication of head and neck radiation therapy, chemotherapy, and HCT as reported by patients (2–6). In many patients, oral mucositis is cancer therapy dose- and rate-limiting, which can lead to modification, delay, or cessation of cancer therapy and ultimately impact cure rates (7,8). Management of oral mucositis may have significant costs because of the need for systemic opioids, parenteral nutrition, antibiotics, and hospital utilization. The reported costs of oral mucositis range from $12,000 up to $42,000 per patient in studies of solid tumor chemotherapy associated with thrombocytopenia (9) and in HCT (7), respectively.

It is common to use systemic opioid analgesics in the management of pain from oral mucositis. Systemic doxepin, a tricyclic antidepressant, has also been used in the pain management of patients with chronic pain (10–13). Tricyclics, including doxepin, lead to increased serotonin and norepinephrine in neuronal synapses that may affect mood and pain (10–12). In addition, tricyclics have been shown to be potent sodium channel blockers (14) and may inhibit spinal N-methyl-d-aspartate receptors (15). Peripheral activity may occur at the adenosine-, H1-, and H2-receptors as well as via enkephalin-like activity (16).

Currently, the topical measures available for management of mucosal pain include topical anesthetics and coating drugs. However, in our 2001 study (17), topical doxepin suspension was shown to produce a reduction in oral pain by more than 50% in cancer patients with extended duration of action. This prior study enrolled patients with either oral mucosal pain from cancer or cancer therapy. We continued to enroll patients with oral mucositis pain attributable solely to cancer therapy. The purpose of this study was to assess the effect of doxepin suspension in the pain management of cancer patients with oral mucositis and to assess variables that may predict the duration of doxepin oral rinse effectiveness.

	METHODS

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Our prior research evaluated 41 patients (37 with pain from cancer therapy, 4 with pain from other causes). To evaluate a homogeneous population we continued to enroll only patients with painful oral mucositis from cancer therapy. We enrolled an additional 14 patients which resulted in a final sample size of 51 patients (29 males, 22 females). All study subjects complied with institutional-approved informed consent.

At the initial visit, an examination of the mouth was conducted by one examiner and oral mucositis was scored using the Oral Mucositis Assessment Scale (OMAS) for all patients. The OMAS assesses erythema severity (none = 0, mild = 1, severe = 2) and ulceration size (none = 0, <1 cm = 1, 1–3 cm = 2, >3 cm = 3) in 9 oral sites (18). Oral pain was reported using a visual analog scale (VAS), which was anchored with "no pain" and "the worst pain possible" at 0 and 10, respectively. Before rinsing, patients were asked to grade their current oral pain on the VAS, when eating (intake of food within 4 h of rinsing), and when at rest (when not eating or speaking). Doxepin suspension (5 mg/mL) was prepared in an oral rinse containing 0.1% alcohol and sorbitol. Administration was supervised in the clinic and subjects rinsed with 5 mL of the solution in their mouth for 1 min and expectorated. No changes were made in previous pain management, as we sought to determine the additional effect of doxepin rinse whether or not systemic analgesics had been initiated. These analgesics were classified as non-opioid, mild opioids, or strong opioids according to the World Health Organization analgesic ladder (18). Patients assessed their pain at 5, 15, 30 min, 1 h, and continuing every 30 min up to 3 h, and finally at 4 h after rinsing. Patients also reported their assessment of the rinse’s taste, discomfort/burning sensation associated with its use, level of fatigue, and VAS pain when eating and when at rest (when not speaking or eating), within 4 h of rinse application.

Statistical analysis was conducted using SAS 9.1 for Windows (SAS, Cary, NC). Both parametric and nonparametric statistics were used to report patient characteristics where appropriate. The Wilcoxon’s signed rank test was used to test for a difference in pain scores because pain was not normally distributed. Both the average and maximum reduction of pain during the period of effectiveness was calculated for each patient in absolute and relative terms. To determine if these reductions in pain were not only statistically significant but clinically meaningful, we also reported what proportion of our sample reported at least some, 25%, 50%, 75%, and 100% reductions in pain. We defined the duration of pain reduction as the time from when the first reported pain score was lower than baseline to the time when reported pain reached or exceeded baseline. This duration variable was right-censored, as many patients still had pain reduction after the study time period ended at 4 h. Therefore, the duration of pain reduction was examined using survival analysis.

Survival analysis was performed using a Cox-proportional hazard model. This robust and widely used semi-parametric model (19) allowed the analysis of how multiple factors influenced the recurrence of baseline pain levels. This rate of recurrence was represented by the hazard function as modeled below:

where x₁, ..., x_k were the predicting variables, b₁, ..., b_k were the parameters to be estimated, and H₀(t) was the baseline hazard at time t. Dividing both sides by H₀(t) and taking the logarithm on each side of the equation, allowed us to generate parameter estimates without having to calculate the baseline hazard. We derived the Cox model parameters using a maximum partial likelihood estimator. We calculated the hazard ratio for each variable by exponentiating its respective regression coefficient. In our model, the hazard ratio represented the relative risk of pain recurrence when changing a particular variable one unit and holding all other variables constant.

We identified clinically meaningful variables to be included in the Cox proportional hazard model a priori. These variables included baseline pain, prior analgesic/anesthetic use and strength, baseline erythema and ulceration measurements, the average and maximum reduction in pain scores after oral rinsing, and the level of reported fatigue after taking the rinse. We also controlled for age and sex.

After accounting for collinear variables, we defined an appropriate multiple Cox regression model. We tested the proportionality assumption of the Cox proportional hazards model. This assumption allows the effect of each covariate to be constant at all points in time. To test this assumption, we added time-interaction terms into the model for each covariate separately and together. If the time-interaction terms in this model were significant, we concluded that the proportional hazards assumption was violated for that variable and the hazard ratio actually represented the average effect of that variable over the time period, instead of the constant effect assumed. However, this was not distressing because this estimation method is considered robust, and we specified our model using clinical reasoning to mitigate misspecification. Taken in context, we concluded that violations of this assumption would not impact our conclusions or interpretations (19).

	RESULTS

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Characteristics of the subjects, their tumor diagnosis, and cancer treatment are shown in Table 1. Fifty-one subjects participated (29 males, 22 females), with an average age of 58.5 (sd, 15.8) yr. The OMAS was used to characterize mucositis severity. In this study, the average patient had a maximum ulcer size score of 1.96 (sd, 0.85) and a peak erythema severity score of 1.61 (sd, 0.63).

A significant reduction of oral pain was recorded after doxepin was administered. At 5 min, on average, patients reported a 41% (P < 0.0001) decrease in pain, obtaining a 55.6% (P < 0.0001) reduction in pain from baseline at 15 min (Fig. 1). Only 5 patients (9.8%) did not report a reduction in pain. Of those who reported lower pain scores at some time point, 38 (83%) saw a reduction in pain at 5 min, whereas 6 patients (13%) first reported reduced pain at 15 min, and 2 patients (4%) finally reported less pain at the 30- and 60-min time points, respectively. The median duration of pain reduction lasted for almost 2 h (Table 2). Over the duration of pain reduction, the median subject reported an average relative pain reduction of 51% and a maximum pain reduction of 75% (both P < 0.0001) (Table 2). To interpret these findings we calculated the proportion of our sample achieving certain threshold reductions in pain and found that 88%, 63%, 24%, and 16% reported 25%, 50%, 75%, and 100% pain reduction, respectively (Table 2).

View larger version (30K): [in this window] [in a new window]   Figure 1. Pain scores after doxepin rinse. Boxplots for the pain scores over time.

Pain recurred slowly and when observation ended at 4 h there was still a 20% (P = 0.0119) reduction in median pain levels (Fig. 1). Nineteen patients (37%) continued to experience pain reduction when the study ended at 4 h and were thus treated as right censored observations (Fig. 2). Furthermore, pain associated with eating was significantly lessened after oral rinsing (P < 0.0001).

View larger version (3K): [in this window] [in a new window]   Figure 2. Survival plot of pain reduction after doxepin rinse (Kaplan-Meier Survival Curve).

For the model, we evaluated variables we considered clinically meaningful and that we thought may predict the pain effect of doxepin suspension. As can be expected, measures of erythema and ulceration were highly and significantly correlated, as were the average and maximum reductions in pain (in absolute and relative terms). To avoid problems associated with multicollinearity, we chose to only include the maximum erythema score because it was more correlated with the dependent variable and the maximum relative reduction in pain and because we felt it was the most important pain reduction measure from the patients’ perspective. We were unable to include the World Health Organization classification of analgesic strength because we did not have enough patients within in each strength classification. Therefore, we just assessed the use of any pain reliever at the time of the clinical trial.

Significant predictors of pain reduction after oral rinsing were baseline pain, the worst erythema severity score, and the relative maximum reduction in pain. The overall final model (Table 3) was statistically significant in explaining the probability of the duration of lower pain scores. Global null hypotheses tests concluded that at least one of the covariates was not zero in this model (P < 0.0001).

The hazard ratios {exp(b_i)} from the Cox proportional hazards model determined that holding all other variables constant, an increase by one unit in baseline VAS pain, the worst documented erythema score, or the relative maximum reduction of pain, decreased the rate of pain recurrence by 34%, 60%, or 3%, respectively (Table 3). The P values for each variable in the model were 0.0054, 0.0002, and >0.0001 respectively. The proportionality assumption did not hold for all variables included in the model, which resulted in hazard ratios explaining the average effect over time rather than a constant effect.

Potential side effects of oral rinsing were recorded as shown in Table 4. Of the sample, 82.4% percent reported some taste other than the "best possible taste"; however, the median taste reported was a neutral 5. Discomfort or burning with oral rinsing was minimal. Sixteen patients (31.4%) reported some discomfort or burning, which was mild (median score VAS = 2). Fatigue was reported in 58.8% of the sample (median score of VAS = 6). It should be noted that fatigue was not recorded before rinsing at baseline, resulting in no control for this variable.

	DISCUSSION

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
Oral mucosal pain resulting from mucositis is a frequent finding in patients receiving head and neck radiation, chemotherapy, or HCT for the treatment of cancer. Topical drugs such as topical anesthetics, analgesics, and coating drugs have been used in cancer patients to manage mucosal pain. Many have suggested that these topical drugs may reduce the need for use of systemic pain relievers (17,20–26). However, topical anesthetics have a short duration of effect (<30 minutes) and may cause oral numbness, taste loss, and burning when rinsing on damaged oral mucosa, which may impact oral function after oral application (17,21–22). The duration of effect of doxepin rinse has been related to a short period of anesthesia, followed by an extended period of analgesia (24). Preliminary studies of oral rinsing with morphine have shown a topical effect in patients with oral cancer pain, although further clarification of dose and side effects are needed (22,25,26). Benzydamine rinse has been shown to reduce pain in patients with oral mucositis (21,22).

The prior study of topical doxepin suspension displayed encouraging results, as VAS pain decreased 50% after rinsing (P < 0.01); however, in this study patients with oral pain from cancer or cancer therapy were recruited (17). Only patients with oral mucositis from cancer therapy were recruited in the current study, resulting in a study of a more homogenous population.

In this study, we reported evidence that topical doxepin rinse is effective in reducing pain for patients with oral mucosal pain from cancer therapy. Forty-six (90%) of the 51 patients reported a reduction in pain after rinsing with doxepin. Pain reduction was highly statistically significant in the first 15 minutes after rinsing with doxepin (P < 0.0001) and at the height of pain reduction, the average patient reported 70% less pain compared to baseline (P < 0.0001). Four hours after rinsing, 19 patients (37%) still reported continuing pain reduction on the VAS (P = 0.012). These results suggest that a single topical doxepin rinse has a promising ability to provide pain reduction exceeding 4 hours in some patients with oral mucositis (Figs. 1 and 2). The biology of pain in oral mucositis is poorly defined, but the effectiveness of doxepin in this study supports the possibility that the pain experience may have a neuropathic component.

We modeled the duration of effectiveness to determine which patient characteristics were associated with a longer duration of pain reduction. We identified three covariates that were highly significant in predicting the rate at which pain recurred in patients with oral mucositis after a single application of doxepin rinse. The severity of oral mucositis, as measured by the worst erythema score, was positively correlated with the duration of pain reduction. Results from the Cox proportional hazards model showed that an increase in erythema severity (none, mild, severe) increased the probability of longer pain reduction (P = 0.0054). It should be noted that the presence and size of mucosal ulceration was highly correlated to erythema severity (r = 0.57; P < 0.0001) and showed the same trend regarding duration of pain reduction. This suggested that doxepin could provide the longest reduction of pain in those with worse mucositis. Doxepin also had a longer duration of effect in patients who reported greater baseline pain (P = 0.0002), suggesting that doxepin can be used to treat patients who are most affected by pain associated with oral mucositis. Finally, the relative maximum reduction of pain after rinsing was the most significant indicator of duration of pain reduction (P < 0.0001) in this population. Therefore, those patients who saw a larger relative reduction in pain continued to report longer duration of pain reduction over the course of follow-up. This finding is intuitive because patients for which doxepin was effective in reducing pain would also see extended duration of pain reduction.

We also included other clinical variables in the analysis that we a priori thought may influence the duration of effect. The variable that represented whether or not the patient was taking pain medication before the study and the variable reporting fatigue after taking the rinse had P values close to the 0.05 significance level. Because of this, we felt that it was not appropriate to make a statement about how prior analgesic/anesthetic use and fatigue levels affected the duration of pain reduction. Because of the small number of patients receiving analgesics and anesthetics, we combined these pain relievers together for analysis. Therefore, further study of these effects is warranted.

The doxepin rinse was generally well accepted by patients with oral mucositis. Taste was acceptable and discomfort/burning with use was minimal. These findings are in contrast to typical complaints of taste and discomfort/burning associated with topical application of local anesthetics. Fatigue was reported by approximately half of patients, with a moderate median degree of fatigue. The interpretation of fatigue is limited by the lack of a baseline fatigue assessment and because fatigue is a common complaint in patients particularly in later stages of cancer therapy (2–5,7–9) at the time of most severe mucositis (2–5). Topical doxepin cream (3.3%) was reported to cause drowsiness in approximately 15% of 200 patients in a study of neuropathic pain (27). Another study of 5% doxepin applied to the skin caused sedation, which then resulted in a reduction in dosage (16). No other side effects were reported in our study.

The results of this study should be reviewed with caution, as this was a single-dose study of consecutive patients and not a randomized, controlled trial. The results may be confounded with other variables that were not controlled for. Future studies should be blinded using a placebo and compared with topical local anesthetic rinses. Another limitation in the original study design was that almost half of the data were censored because the study did not follow patients until all pain reduction subsided. To combat this limitation, we used a Cox proportional hazard model to help determine which patients were likely to maintain pain reduction longer. Future studies should attempt to limit the need for survival analysis by following patients for a longer time period to account for prolonged pain reduction.

The results of this study suggest that this doxepin oral rinse may be a useful medication for management of oral mucosal pain. The longest duration of pain reduction after oral doxepin rinse was identified in those with more severe erythema, those with greater baseline pain, and those who received the largest relative reduction in pain after rinsing. We encourage future work to asses the effect of concurrent systemic analgesic use, potential systemic absorption after oral rinsing, and the impact of repeated dosing.

	Footnotes

 
Accepted for publication April 4, 2006.

	REFERENCES

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Epstein, J. B. Articles by Truelove, E. L. Search for Related Content PubMed PubMed Citation Articles by Epstein, J. B. Articles by Truelove, E. L. Related Collections Complications Pain