Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:
1. Summarize the diagnosis of vulvodynia based on the multisocietal consensus definition.
2. Differentiate among the benefits, limitations, and adverse effects of different topical therapies for vulvodynia.
3. Outline the integration of topical therapy into a multimodal treatment regimen for vulvodynia.
Vulvodynia is defined as vulvar pain lasting at least 3 months without a clear identifiable cause but potential associated factors. This definition is a result of a multisocietal (International Society for the Study of Vulvovaginal Disease, International Society for the Study of Women's Sexual Health, and International Pelvic Pain Society [IPPS]) consensus published in 2015.1 As it has been studied over time, this condition has also been referred to as "vulvar dysesthesia," "vulvar vestibulitis," and "vestibulodynia."1,2 Patients with vulvodynia may experience vulvovestibular burning, stinging, itching, irritation, tenderness, or any combination of these.2 The 2015 consensus guidelines for vulvodynia further characterize the condition based on its location (localized or generalized), provocation (provoked or spontaneous), onset (primary vs secondary), and temporality (persistent, constant, intermittent, immediate, or delayed). Definitions of these vulvodynia descriptors were released in an addendum to the 2015 consensus guidelines in 2019.3
The burden of vulvodynia extends beyond pain. Vulvodynia negatively impacts patient sexuality, including desire, arousal, frequency of intercourse and orgasm, and satisfaction. Patients experiencing sexual pain and their partners are reported to have lower relationship satisfaction. Patients with vulvodynia can have significant mental health challenges, reporting high rates of depression, anxiety, low self-esteem, and poor body image.4 Seeking treatment is an additional burden in terms of both time and money. Patients visit an average of 5 health care providers before even receiving a diagnosis.5 Based on studies in the United States, at least 16% of women suffer from vulvodynia.2 There is a substantial economic burden due to costs of medical care, medications and other therapy, and time missed from work. A study by Xie et al6 estimated the annual cost of vulvodynia to be $31 billion to 72 billion in the United States.
There is no known singular cause of vulvodynia. However, there are some potential predisposing factors associated with the disease, including genetic influences, frequent yeast infections, inflammatory disorders such as lichen sclerosus, hypoestrogenism, neuropathic pain, hypertonic pelvic floor disorders, and certain psychiatric diagnoses.2 Likewise, there are multiple theories behind the pathogenesis of vulvodynia. Bohm-Starke et al7 suggest that it is due to increased sensitization of peripheral vestibular nerves. Various inflammatory markers such as interleukins and mast cells have been demonstrated in increased concentrations in the tissue of patients with vulvodynia according to Foster and Hasday8 and Nyirjesy et al.9 Low testosterone and vaginal atrophy associated with low-dose oral contraceptive pills (OCPs) have also been implicated in vulvodynia by Burrows and Goldstein.10
Over the years, treatment for vulvodynia has included both nonpharmacologic therapies and various medications to target these mechanisms. Nonpharmacologic approaches include cognitive behavioral therapy (CBT), pelvic floor physical therapy, acupuncture, and biofeedback techniques, and surgical removal of the tissue that is the source of pain (partial vestibulectomy).11-14
Pharmacologic therapies include such agents as gabapentin for neuropathic pain,15 antidepressants for the antinociceptor properties of serotonin and norepinephrine,16 anti-inflammatories (corticosteroids and nonsteroidal anti-inflammatory drugs), muscle relaxants,17 and hormonal therapy.10 Many of these agents are employed in either oral or topical form. The benefit of topical therapy is the avoidance of adverse effects, which often accompany systemic administration of medications. Patients may also be more comfortable with topical forms of these medications due to the stigma surrounding the use of the types of medications prescribed (antidepressants, pain medications, and benzodiazepines).16 Injections of local corticosteroids and anesthetics, interferons, and botulinum toxin have also been described.18-20
This article focuses on the available evidence to support the use of topical therapies for the treatment of vulvodynia. Review of the literature did not reveal comprehensive and updated articles on this topic. The objective of this review is to summarize and appraise the available research to aid clinicians in the treatment of vulvodynia.
Methods
The literature review was conducted using the PubMed Advanced Search Builder. Both MeSH terms and keywords were used, including vulvodynia, vestibulodynia, vulvar vestibulitis, and a list of known pharmacologic agents used in the treatment of vulvodynia. Articles were excluded from the review if they were unrelated to vulvodynia or did not discuss topical treatments.
Results
Based on the PubMed search query above, 119 publications were identified. Upon more in-depth review, 30 of these were specific to the topical treatment of vulvodynia. Additional articles were located through Cochrane Library and Google Scholar searches. A total of 36 articles consisting of 15 randomized controlled trials (RCTs), 19 nonrandomized studies, and 2 case reports were included in this review.
Discussion
Topical pharmacologic treatment for vulvodynia falls into 4 categories: local anesthetics, anti-inflammatories, antidepressants, and other drugs. Each of these aims to target pain modulation or pathologies implicated in vulvodynia such as inflammation, muscle spasm, or hormone imbalance.
Local Anesthetics
One theory as to the cause of vulvodynia is that it may be attributable to peripheral nerve pathology in the vulvar region. Local anesthetics such as lidocaine block these mucocutaneous nerve endings by preventing conduction of action potentials in nerve axons.21
Five RCTs and 2 nonrandomized studies have tested various regimens of topical lidocaine (Table 1). Topical lidocaine 5% cream 4 times daily for 12 weeks administered to 112 patients by Foster et al22 failed to demonstrate a significant decrease in pain on tampon insertion over placebo, either in combination with oral desipramine or alone. Another RCT, by Danielsson et al,13 investigated the efficacy of electromyography (EMG) biofeedback and topical lidocaine. Patients were instructed to use the lidocaine 2% gel for 2 months and then lidocaine 5% ointment for the following 2 months, applying it 5 to 7 times per day. The EMG biofeedback sessions were to be performed 3 times a day. Although there were no differences between the EMG and lidocaine groups, both treatments produced a statistically significant increase in pain threshold (EMG: P = 0.002, lidocaine: P = 0.008) and improved sexual function and quality of life (EMG: P = 0.001, lidocaine: P = 0.002).13 This study was limited by poor patient compliance with all treatment regimens. Bohm-Starke et al23 demonstrated similar results with EMG biofeedback twice daily and topical lidocaine (2% gel or 5% ointment 5 times daily) for 4 months. Both treatments produced increased pain thresholds (P < 0.001). However, they attributed some of the positive response to placebo effect and the acquisition of better pain-coping strategies during treatment.
In studies by Bergeron et al11 and Morin et al12 that compared 10 to 12 weeks of cognitive behavioral couple therapy (CBCT) and physical therapy (PT) to nightly lidocaine 5% ointment, both outperformed the topical agent in improving pain and sexual function using several numeric rating scales (CBCT: P < 0.001, PT: P < 0.001). A prospective nonrandomized trial by Zolnoun et al24 in which 61 patients were treated with nightly lidocaine 5% ointment for 6 to 8 weeks, 54% of patients experienced a more than 50% decrease in dyspareunia and there was a statistically significant improvement in intercourse-related pain (P < 0.001) and daily pain (P = 0.004). Unfortunately, patients were less likely to respond to therapy if they had comorbid interstitial cystitis or other vulvar conditions.24
In a prospective nonrandomized study by Nyirjesy and Halpern,25 18.1% of patients had a positive response to application of aqueous lidocaine 4% before intercourse. In numerous noncontrolled trials (see Table 1), topical lidocaine has shown a significant benefit in a maximum of 54% of patients, and the only double-blinded RCT did not show any benefit. It is important to take into consideration that any benefit must also be weighed against the adverse effects of topical lidocaine, including local irritation at the application site, exacerbation, or rebound effect. Without further studies, topical lidocaine is not recommended for long-term management of vulvodynia.5,26
Capsaicin has anesthetic properties in its ability to desensitize vanilloid receptors, which have been demonstrated in increased density in the vestibular tissue of patients with vulvodynia.5 Two prospective non-controlled studies examined the utility of capsaicin in treatment of vulvodynia (Table 2). In the first study, by Steinberg et al,27 patients treated with 0.025% capsaicin cream for 20 minutes daily for 12 weeks had a significant improvement in pain on touch test (P < 0.001) and dyspareunia (P < 0.001); however, these results were confounded by pretreatment with topical lidocaine. The authors noted a lack of long-term follow-up data and information on patients who discontinued therapy, and recommended larger, controlled studies of a more heterogeneous sample of patients.27 The second study, by Murina et al,28 demonstrated that 59% of patients treated with a tapering regimen of topical capsaicin 0.05% for 6 months experienced improvement in symptoms, but all had recurrences after therapy cessation. Resumption of therapy resulted in improvement again.
Capsaicin cannot be used indefinitely, as there is burning with application, which can be significant, but perhaps a higher concentration or more frequent application is needed. Additional studies are needed to help identify optimal concentration and dosing frequencies. Regardless, according to the authors of the study, capsaicin may be considered as a "last choice" medical approach.28 According to an expert committee at the Fourth International Consultation on Sexual Medicine, capsaicin should only be considered for treatment if other agents fail or offered as an alternative to invasive surgery.26
Anti-inflammatory Medications
Corticosteroids are used for their anti-inflammatory properties as various inflammatory markers can be upregulated in the vulvar tissue of women with vulvodynia.8 Three RCTs and 2 nonrandomized studies investigated various topical corticosteroid regimens (Table 3).
A randomized double-blinded crossover study by Munday29 demonstrated that 73% of patients had improved pain, tenderness, and erythema with nightly clobetasol propionate 0.05% for 1 month, and 60% had improvement with nightly hydrocortisone 0.5% for 1 month. Unfortunately, only 14 out of 22 patients completed both arms (others were excluded for violating the protocol).29
In an RCT by Bergeron et al30 comparing hydrocortisone 1% cream 3 times daily to group CBT for 13 weeks, both groups achieved significant reductions in pain and improved sexual activity, although the improvements were significantly greater with group CBT (pain: P = 0.039, increased intercourse frequency: P < 0.01). The authors speculated that group CBT may impact more dimensions of dyspareunia than a topical corticosteroid, including pain catastrophizing and sexuality.30
In another RCT by Brown et al,31 nightly triamcinolone 0.1% cream in conjunction with daily oral amitriptyline 10 to 20 mg for 6 weeks did not reduce pain in patients with vulvodynia, although CBT, physical therapy, and sex therapy did, as subjectively reported by the pain questionnaire. In a nonrandomized trial by Nyirjesy and Halpern,25 33.8% of patients treated with desoximetasone 0.25% at various frequencies and durations experienced an unspecified positive response. Sonnex32 tested multiple corticosteroid classes: 46% of patients treated with the mild/moderate corticosteroid clobetasone butyrate 0.05% had some improvement (5% had marked improvement) and 48% of patients treated with the potent corticosteroid clobetasol 0.05% had some improvement (19% with marked improvement) after administration at an unspecified frequency for 6 to 8 weeks. Although more controlled studies are needed, available data suggest a modest improvement with use of topical corticosteroids. One should note that high-dose corticosteroids are not recommended for long-term use due to potential adverse reactions such as skin thinning.
The nonsteroidal anti-inflammatory drug meloxicam produced a reduction in pain scores for 6 out of 8 patients treated with meloxicam 3% gel twice daily in a study by Kim et al33 (Table 4). These results, however, cannot be extrapolated due to the small sample size, poor controls, pretreatment with lidocaine, and treatment duration of only 1 week. Although not a topical agent, another medication with anti-inflammatory properties is enoxaparin. In an RCT of 40 patients treated daily with enoxaparin 40-mg subcutaneous injections or saline placebo for 90 days, there was a statistically significant reduction in pain over placebo in those treated with enoxaparin (P = 0.004) (Table 4). Seventy-five percent of patients treated with enoxaparin reported a reduction in pain greater than 20% compared with only 27.8% of those treated with placebo.34 Bruising and abnormal bleeding are possible side effects of enoxaparin, but no significant side effects were reported. Larger studies are needed to follow these modest improvements in pain.5
Because vulvar biopsies of patients with vulvodynia exhibit increased mast cells, Nyirjesy et al9 studied the effect of cromolyn, a mast cell stabilizer (Table 4). Twenty-six patients were randomized to cromolyn 4% cream or placebo 3 times daily for 3 months. Although 38% of patients treated with cromolyn had at least 50% improvement in dyspareunia and vestibular tenderness, it performed worse than placebo (46% of patients treated with placebo had at least 50% improvement). Eight patients withdrew due to persistent symptoms, self-treatment with other medications, or diagnosis of candidiasis or desquamative inflammatory vaginitis. Two patients experienced stinging with application.9 Larger studies are needed to determine the theoretical efficacy of cromolyn.5
Antidepressant Medications
Antidepressants can inhibit pain via modulating nociceptor signaling by increasing the release of inhibitory neurotransmitters like norepinephrine and serotonin. One RCT and 3 nonrandomized studies analyzed the effect of topical amitriptyline (Table 5). The only study to test topical amitriptyline on its own was a prospective nonrandomized trial by Pagano and Wong.16 Of 150 patients treated with topical amitriptyline 2% twice a day for 3 months, 56% had improvement in symptoms and 10% overall had a complete response, including those with severe dyspareunia. However, 44% had no improvement, including 16 patients who discontinued therapy due to irritation from the medication.16 The authors recommend using a lower dose of an oral antidepressant in conjunction with a topical cream to mitigate the systemic effects like drowsiness from oral medications.16 In a retrospective chart review, Ruoss et al35 analyzed the response to once- or twice-daily application of 0.5 mL of topical amitriptyline 0.5%/estriol 0.03% in patients with vulvodynia, dyspareunia, and pudendal neuralgia. Depending on age group, between 51% and 66.7% of patients responded to therapy, and 64.4% noted an improvement in dyspareunia. Of note, 17% of patients experienced stinging with application.35 Although there are favorable effects in many patients who are able to tolerate or do not experience stinging with application, controlled studies of topical amitriptyline are needed to determine the optimal concentration of medication required to provide the most relief of symptoms with the least amount of irritation.
Two other studies tested amitriptyline in combination with other drugs. In a double-blinded, placebo-controlled RCT by Bonham et al,36 9 patients were treated with amitriptyline 2%/baclofen 2%, gabapentin 6%, ketamine 10%, loperamide 5%, and Cetaphil (as placebo) twice a day for 2 weeks each, and none of the agents produced a statistically significant improvement in pain. They suggested that moisturizer alone may be beneficial.36 In a retrospective study, Nyirjesy et al37 demonstrated marked improvement in 53% of patients treated with amitriptyline 2%/baclofen 2% cream twice daily for 4 to 6 weeks, though 29% reported little or no improvement, and 11% discontinued therapy due to lack of improvement or burning secondary to treatment. Overall, there was a significant decrease in symptoms that had interfered with social activities (P = 0.017) and intercourse (P = 0.05).37 More controlled studies of these drug combinations are needed.
Anticonvulsant Medications
Gabapentin has been employed in vulvodynia therapy for its properties in treating neuropathic pain. Gabapentin inhibits voltage-gated calcium influx in neurons thereby preventing release of the nociceptive neurotransmitter glutamate.38 Two nonrandomized studies and 1 case report investigated the use of topical gabapentin (Table 6). Hiom et al15 studied the effects of gabapentin 6% gel of unspecified frequency for 1 month in patients with neuropathic pain, 4 of whom had vulvodynia. The reduction in pain scores post-treatment was statistically significant (P < 0.001). All 4 patients with vulvodynia had a positive response and the formulation was deemed to be safe.15 In a nonrandomized study by Boardman et al,39 35 patients were treated with topical gabapentin 2% to 6% cream 3 times daily for 8 weeks and tolerated the medication well. Eighty percent reported improvement in pain of at least 50%, and 29% had complete relief. Fourteen percent discontinued therapy for unknown reasons. In a case report by Verstraelen et al,40 a patient with vulvodynia due to genitofemoral neuralgia failed treatment with the oral antidepressants nortriptyline and venlafaxine. The effects of topical lidocaine also did not last in this patient. However, the patient remained pain free at 1 year after treatment with gabapentin 6% cream twice a day and oral duloxetine daily.40
Although the results from these studies are promising, larger, more controlled studies are needed for gabapentin, and other anticonvulsants such as pregabalin, carbamazepine, and lamotrigine.5
Antispasmodic Medications
Medications used to treat muscle spasms have also been studied. Muscle spasms can occur in response to local inflammation, muscle injury, or other pathology. Diazepam inhibits neuronal depolarization (and therefore skeletal muscle spasm) by triggering the influx of chloride ions when acting as a [gamma]-aminobutyric acid type A (GABA-A) receptor agonist. Vulvodynia is often complicated by high pelvic floor muscle tone in many patients. Research has shown that patients with vulvodynia have significantly higher pelvic floor tone than those without.41
Three RCTs and 2 nonrandomized studies examined vaginal diazepam (Table 7). In an RCT by Murina et al,42 patients were treated with transcutaneous electrical nerve stimulation (TENS) alone or with the addition of vaginal diazepam. Those treated with 5-mg vaginal diazepam nightly for 60 days experienced a significantly greater decrease in dyspareunia (P = 0.05) and improvement in pelvic floor muscle relaxation (P < 0.01) compared with those treated with TENS alone. In addition, both groups experienced a decrease in pain based on the visual analog scale but there was no statistically significant difference between groups on this measure.42
In an RCT by Crisp et al,43 in which patients with hypertonic pelvic floor muscles were treated with 10-mg diazepam suppositories or placebo nightly for 28 days, diazepam failed to produce a difference in pelvic floor tone, pain, or sexual function. Holland et al44 treated 35 patients with pelvic pain in the same manner, and again diazepam 10-mg suppositories failed to improve pain or other symptoms. In a retrospective study by Rogalski et al,45 26 patients were treated with high-tone pelvic floor dysfunction (80.7% had vestibulodynia) with 10-mg diazepam suppositories nightly for 30 days, in addition to pelvic floor physical therapy and intramuscular trigger point injections. Patients experienced an improvement in pain on physical examination (P = 0.017), sexual function (subjectively), and pelvic floor tone (P < 0.001), but it is impossible to discern if this effect was attributable to diazepam because there were no controls.45
In another nonrandomized trial by Carrico and Peters,41 21 patients were treated with 2- to 10-mg vaginal diazepam every 8 hours as needed for 8 weeks and 71% reported improvement. However, the improvement in pain post-treatment on the visual analog scale was not statistically significant.41 In summary, the evidence for diazepam is equivocal. Noncontrolled studies showed mostly subjective improvement, but controlled studies failed to show a significant reduction in pain.17,46 Further, although vulvodynia and pelvic pain/hypertonia are related, 2 of these RCTs included patients without a specific diagnosis of vulvodynia. As vaginal diazepam is well-tolerated, additional controlled studies should be pursued.
Baclofen is a [gamma]-aminobutyric acid type B (GABA-B) receptor agonist and may also produce antiglutamate action, both of which inhibit nociceptive signaling in cutaneous nerve fibers. It is most appropriate for use in patients with concurrent pelvic hypertonia.47 In the study by Nyirjesy et al (Table 5), 53% of patients treated with amitriptyline 2%/baclofen 2% cream twice daily for 4 to 6 weeks experienced marked improvement.37 In the RCT by Bonham et al (Table 5), 9 patients were treated with amitriptyline 2%/baclofen 2%, gabapentin 6%, ketamine 10%, loperamide 5%, and Cetaphil twice a day for 2 weeks each, and none of the agents produced a statistically significant improvement in pain.36 In a case report by Hesselink et al,47 a patient with vulvodynia and proctodynia was treated with topical baclofen 5% and oral palmitoylethanolamide 3 times daily for 3 months (Table 7). The patient experienced 50% improvement in her symptoms, and she was able to engage in sexual activity again.47 Palmitoylethanolamide has anti-inflammatory properties and can inhibit overactive mast cells that produce neurotrophic growth factor, which functions to sensitize nociceptors. Hesselink et al48 recommend a topical palmitoylethanolamide 1% in combination with baclofen 5% but did not report on the efficacy of this regimen.
Hormonal Agents
It has been hypothesized that atrophy from hypoestrogenism and low testosterone contribute to vulvar pain in vulvodynia.10 Four nonrandomized studies employed topical estrogen and/or testosterone in the treatment of vulvodynia (Table 8). When Burrows and Goldstein tested this hypothesis by treating 50 patients taking OCPs with estradiol 0.01%/testosterone 0.1% cream twice daily for an average of 20 weeks, a statistically significant decrease in pain was observed (P = 0.001).10 This improvement was in the setting of cessation of OCPs. If symptoms began while taking oral contraceptives, it is reasonable to consider using topical estradiol/testosterone and stopping the contraceptive if feasible.5
Similarly, Mitchell et al49 suggested an association between spironolactone and vulvodynia. Of 7 premenopausal patients who developed vulvodynia while taking spironolactone, all had improved pain and sexual function upon cessation of spironolactone and application of estradiol 0.01%/testosterone 0.1% twice daily for 3 to 4 months. Of note, 5 of the 7 patients were also taking OCPs, making it difficult to discern whether OCPs need to be discontinued for the topical therapy to be effective.49
In a noncontrolled study by Greenhouse and Harte,50 over 80% of premenopausal patients with introital dyspareunia treated with estradiol 25 [mu]g for 10 weeks had moderate or complete relief of symptoms. In another study by Gardella et al,50 34 patients with interstitial cystitis/bladder pain syndrome (of which, 94.1% had vulvodynia), 0.5-mg estriol cream applied 3 times weekly for 12 weeks produced significant improvement in urinary and sexual function (P < 0.001 for both). This regimen may be appropriate for patients with comorbid urinary symptoms. Topical estrogen therapy should be strongly considered as first-line therapy in symptomatic postmenopausal women with findings of genital syndrome of menopause. Vulvodynia is not necessarily hormonally related in every patient, but it may be appropriate to use topical estrogen as an adjunct to therapy in any patient with signs of vaginal atrophy or who is on treatment, which may lower estrogen levels.
Vasodilators
Both chronic anal fissures and vulvodynia can involve hypertonic muscle and inflammatory infiltrate. As nifedipine is used for chronic anal fissures, Bornstein et al52 tested its use in patients with vulvodynia (Table 9). However, the authors demonstrated that application of topical nifedipine 0.2% to 0.4% 4 times daily for 6 weeks was no better than placebo in reducing pain.52 Nitroglycerin 0.2% cream, also used for anal fissures, was administered to 34 patients 3 times weekly for 4 to 6 weeks in a nonrandomized trail by Walsh et al.53 There was a statistically significant decrease in pain intensity (P < 0.000) and during sexual activity (P < 0.005), but many patients experienced headaches.53 More studies are needed to determine the efficacies of these 2 drugs.
Conclusion
Vulvodynia is a significant medical entity that affects millions of women worldwide with substantial physical, psychological, and financial implications. Various therapies with different mechanisms of action and modes of delivery have been used in the treatment of vulvodynia, with mixed success. This review article focused primarily on topical therapies and their potential usefulness in the treatment of vulvodynia. The advantages of topical agents include avoiding systemic effects like drowsiness, gastrointestinal (GI) symptoms, mental status changes, and anticholinergic effects, which often accompany oral administration, and limiting potentially harmful interactions with other medications. However, patients may experience local reactions to topical therapy and there is limited availability and increased cost associated with topical formulations that often need to be produced by a compounding pharmacy.
Essential to identifying effective therapies for any disease is the use of universally accepted scientific methods, which produce sound evidence-based data, the gold standard of which is the randomized double-blind placebo-controlled study. This can prove quite challenging for vulvodynia due to the diversity of symptomatology and difficulty in diagnosis despite the best efforts put forth in developing a multisocietal definition consensus.1,3 Many of the studies reviewed in this article did not include clear or consistent inclusion criteria, which introduces skepticism as to the diagnosis of vulvodynia and therefore impacts the validity of results and study conclusions. In addition, most of the studies are uncontrolled, limited in size, of short duration, and lack long-term follow up, thus making it difficult to draw conclusions about effectiveness of the therapies studied.
Despite their limitations, based on the results of these studies, the effects of topical corticosteroids, topical gabapentin, and amitriptyline/baclofen cream are all promising. Larger, controlled studies are needed to further demonstrate their efficacy and to determine the appropriate concentrations and frequencies of dosing. It is unlikely that any one medication will be sufficient in the treatment of all causes of vulvodynia. Patients with particular comorbidities may respond better to certain medications targeting those conditions, such as hormones for patients with estrogen deficiency or corticosteroids for patients with vulvar inflammatory conditions. In addition, it may be necessary to try multiple treatments sequentially to identify which agent(s) provide relief of symptoms. Patients likely will benefit most from a combination of medications in addition to cognitive behavioral and physical therapy, although further research into this regimen is needed as well. The challenges in finding relief for vulvodynia sufferers are great, but with the collaboration of academic, private industry, and government-sponsored research, we should continue to push forward in this important endeavor.
References