Michal Lew-Starowicz1
(1)
III Department of Psychiatry, Institute of Psychiatry and Neurology, Warsaw, Poland
Michal Lew-Starowicz
Email: michallew-starowicz@wp.pl
13.1 Introduction
Oncological patients often receive additional medication for conditions related to the cancer itself or related to the adverse effects of cancer treatment. Common concerns include depressive symptoms, pain, nausea, and vomiting. This chapter deals with the impact of medication used to treat these conditions and the influence of other drugs that are in use for different causes in cancer patients like corticosteroids and cannabinoids. Hormonal therapies are addressed in other chapters. Intimacy and sexuality are relevant compounds of the quality of life and may have a special value in people with poor prognosis. Therefore, sexual functioning should be one of the benchmarks in the assessment of the risk–benefit ratio when prescribing additional medication to cancer patients.
13.2 Antidepressants
Depressive and anxiety symptoms may appear at any stage of the disease. After being confronted with the cancer diagnosis or along with changes in body appearance resulting from surgery and adjuvant therapies, patients often present with adjustment disorder. Difficulties related to cancer treatment, physical symptoms, lifestyle changes as well as medication side effects can result in clinically relevant depression or exacerbate a previously existing mood disorder. It can also be a specific side effect of some adjuvant therapies (e.g., interferon, corticosteroids). Common symptoms include depressive mood, loss of energy, diminished interest or pleasure in all or almost all activities, insomnia or hypersomnia, psychomotor retardation or agitation, feelings of worthlessness or guilt, and thoughts of death or suicidal ideation. Depression may also take away hope and motivation, thereby affecting patient’s compliance, especially in the initial and palliative phase of the treatment. Common sexual symptoms include loss of sexual desire and decrease in sexual pleasure.
In a meta-analysis of 94 studies with over 14,000 adults with cancer, Mitchell et al. found that some combination of mood disorders occurs in 29 % of patients in palliative care settings and in 38.2 % of patients in oncological and hematological settings. The most common diagnoses were: depression (16.5 % and 16.3 %, respectively), adjustment disorder (15.4 % and 19.4 %), and anxiety disorders (9.8 % and 10.3 %) [1]. Treatment of depression may improve quality of life in patients with cancer, improve compliance to oncological treatment, and also lessen sexual problems. Antidepressants (ADs) are used as the first-line treatment for depression and anxiety disorders in both general and cancer population. In a survey of prescribing patterns in outpatient oncology settings over a 2-year period, ADs were prescribed in 14 % of the patients [2]. These drugs seem to be safe in cancer patients; however, literature on this topic is scarce with no large controlled trials. Selective serotonin-reuptake inhibitors (SSRI) such as fluoxetine or paroxetine are reported to be well-tolerated and commonly used in cancer patients. In low doses, ADs may also relieve cancer-related pain (especially neuropathic pain) and improve sleep. On the other hand, antidepressants often cause negative sexual side effects and may worsen existing sexual dysfunctions (SDs). Most of the studies on treating depressive symptoms in cancer patients do not monitor treatment-related sexual side effects. Both tricyclic antidepressants (TCAs) and SSRIs may be effective for the treatment of depression but both are also regularly accompanied by diminished sexual desire, orgasmic difficulties, delayed ejaculation, and erectile dysfunction.
Sexual side effects (loss of interest in sex and inability to achieve an orgasm) were found to be two out of the four main reasons for noncompliance in antidepressant treatment in patients with mild to severe depression [3]. Classification of ADs in relation to their potential of inducing sexual adverse effects according to a meta-analysis by Serretti and Chiesa is presented in Table 13.1 [4].
Table 13.1
Antidepressants classified according to their potential for inducing sexual dysfunction [4]
|
Category |
Low potential for inducing SD |
Moderate potential for inducing SD |
Strong potential for inducing SD |
|
Total sexual dysfunction |
Moclobemide (0.22) Agomelatine (0.25) Amineptine (0.46) Nefazodone (0.46) Bupropion (0.75) |
Mirtazapine (2.32) Fluvoxamine (3.27) Escitalopram (3.44) Duloxetine (4.36) Phenelzine (6.43) Imipramine (7.24) |
Fluoxetine (15.59) Paroxetine (16.86) Citalopram (20.27) Venlafaxine (24.82) Sertraline (27.43) |
|
Desire dysfunction |
Selegiline (0.19) Escitalopram (1.1) Bupropion (1.29) Agomelatine (1.52) Nefazodone (1.53) |
Moclobemide (4.11) Duloxetine (5.25) Phenelzine (5.71) Mirtazapine (6.03) Fluvoxamine (6.31) Imipramine (6.35) |
Venlafaxine (23.0) Sertraline (42.95) Fluoxetine (45.59) Paroxetine (46.99) Citalopram (55.30) |
|
Arousal dysfunction |
Nefazodone (0.19) Selegiline (0.26) Escitalopram (0.68) Bupropion (1.83) Moclobemide (1.91) |
Mirtazapine (3.92) Phenelzine (5.76) Imipramine (6.07) Fluvoxamine (7.49) |
Duloxetine (10.95) Fluoxetine (31.42) Sertraline (38.58) Paroxetine (44.44) Venlafaxine (54.04) Citalopram (82.48) |
|
Orgasmic dysfunction |
Selegiline (0.04) Nefazodone (0.32) Moclobemide (0.41) Bupropion (1.26) Agomelatine (1.31) |
Fluvoxamine (2.71) Escitalopram (4.23) Mirtazapine (4.44) Imipramine (5.25) |
Phenelzine (11.85) Fluoxetine (11.91) Citalopram (14.39) Sertraline (15.03) Venlafaxine (15.94) Paroxetine (18.45) Clomipramine (41.89) |
In parentheses: OR compared with placebo (95 % CI)
Compared with SSRIs, there is relatively little literature on the use of “sex-friendly” ADs in cancer patients. Here we mention some of those “sex-friendly” ADs that may be useful when applied with caution:
Agomelatine
melatonergic receptor agonist and 5-HT2c receptor antagonist, usual dose 25–50 mg at bedtime, initially needs transaminase monitoring. There are very limited data about use in cancer patients but it may be useful in women with breast cancer who take tamoxifen. Contrary to SSRIs, agomelatine does not affect tamoxifen metabolism via cytochrome P450 2D6.
Bupropion
dopamine and noradrenaline reuptake inhibitor. It is found to improve sexual outcomes (increase in sexual desire and frequency) but due to its dose-related seizure-inducing potential, it should be avoided in patients with Central Nerve System (CNS) tumors, cranial trauma, history of seizures or taking other drugs that lower the seizure threshold. Usually start with 75–150 mg daily, max dose 450 mg.
Mirtazapine
alpha2-adrenergic receptor and 5-HT2/5-HT3 receptor antagonist, dosing 15–45 mg at bedtime. It is structurally similar to mianserin but has less risk of hematological complications including agranulocytosis, important for patients on chemotherapy. Higher dose may increase the risk of seizure.
Moclobemide
reversible monoamine oxidase inhibitor, generally well-tolerated, reports on sexual function improvement, dose 300–600 mg, should be avoided in patients with pheochromocytoma. It may enhance the effect of nonsteroid anti-inflammatory drugs and opioid analgesics (dose modification might be needed).
Trazodone
serotonin transporter (SERT) inhibitor and 5-HT2 receptor antagonist, peripheral alpha 1-adrenoreceptor antagonist; similar to nefazodone and also with low potential of inducing SD (sale of nefazodone was discontinued in many countries due to hepatic complications while trazodone is still available). Some reports on good outcomes in psychogenic and SSRI-induced ED (dose 150–200 mg). Usually start with dose 50–75 mg and continue up to 450 mg (max 600 mg). May cause sedation and dizziness (less with extended release formulation), higher dose should be used with caution.
Vortioxetine
serotonin receptors modulator and SERT inhibitor with significantly lower potential of treatment-related SDs in comparison with commonly used SSRIs, venlafaxine or duloxetine. Sexual function preservation is explained mainly by 5-HT1a receptor agonism. Usually, start dose 10 mg and max dose 20 mg.
If switching to a “sex friendly” AD is not possible or not effective, adding an antidote to the treatment should be considered. A recent Cochrane Library review indicates the most effective pharmacological interventions for AD-related SD as follows: [5]
· PDE5-inhibitors proved to be effective in restoring erectile function, one study suggested a potential improvement in orgasmic function in female patients
· Improved sexual function in patients who received bupropion 300 mg (150 mg twice daily) added to regular AD treatment
· Switching from SSRI (sertraline) to trazodone
Besides, in cancer patients, depression treatment often remains noneffective if it is exclusively limited to drug prescription. In a recent study in cancer patients with major depression, collaborative care (information on depression and its treatment, brief, intensive problem-solving therapy, behavioral activation, and psychiatry supervised AD medication) was compared with the normal approach by primary care physician or oncologist that included AD medication [6]. The collaborative care had a much stronger positive response (62 % vs. 17 %)
Apart from being less depressive or anxious, patients receiving collaborative depression care also had less pain and fatigue, better functioning, health and quality of life [6]. Relieving depression, anxiety, pain, and fatigue seems to be also beneficial for the patient’s sexual health. In spite of that many psychosocial support programs in cancer care exclusively focus on treatment with ADs that often cause sexual side effects. Oncologist should always consider referral for psychotherapy or supportive counseling of their depressive patients. Psychotherapy, especially the cognitive-behavioral approach and support group, proved to be an effective intervention for cancer patients with depression [7].
13.2.1 Hot Flashes
Breast cancer patients commonly suffer from hot flashes as a consequence of tamoxifen treatment.
Several SSRIs and SNRIs including paroxetine, fluoxetine, citalopram, and venlafaxine effectively reduce the incidence and severity of hot flashes. Unfortunately, all these ADs inhibit CYP2D6 enzyme function, thereby reducing the efficacy of tamoxifen treatment. Paroxetine and fluoxetine have the greatest CYP2D6-inhibiting properties and they should not be used. When an antidepressant of this group seems necessary, venlafaxine and (es)citalopram may be used, as these drugs lead to less or no interference with tamoxifen metabolism.
13.3 Antiemetics
Antiemetics are widely used in cancer patients to overcome nausea and vomiting, common and frustrating side effects of the majority of chemotherapeutics. Relief of these symptoms results in better overall functioning and therefore may improve interpersonal activities including intimacy and sexuality. Drugs that are commonly used with this indication are listed below with comments on their influence on sexual functioning:
· Serotonin 5-HT3 receptor antagonists:
Include: dolasetron, granisetron, ondansetron, palonosetron. Common side effects include headache, hiccups, and constipation, rarely QT prolongation. In clinical studies, there were no reported sexual side effects and no emergent data from patients reports in the clinical practice.
· Steroids
Include: dexamethasone, methylprednisolone. For impact on sexual health – see another part of this chapter.
· Dopamine antagonists
Include: droperidol, haloperidol, metoclopramide, promethazine. Usually given as needed. Common side effects include dry mouth, sedation, constipation or diarrhea, dizziness, and extrapyramidal symptoms (especially in young people). Dopaminergic antagonism may result in hyperprolactinemia (central impact on tubero-infundibular pathway) and related hypogonadism, decreased desire (also through motivation/reward inhibition) and less sexual response (also due to anticholinergic effect). However, these effects are only extrapolated from other populations of patients (mainly psychiatric) and need further confirmation within the oncological setting.
· Anxiolytics
Include: benzodiazepines (most commonly alprazolam and lorazepam). Side effects are mainly related to sedation (fatigue, sleepiness, dizziness), may also cause headache, memory disturbance, and dry mouth. Sexual side effects include decrease in sexual desire, delay in reaching orgasm, and erectile dysfunction. Increased sexual drive due to disinhibition has also been reported. These findings are also seen in nononcological patients and have to be treated with caution.
· Cannabinoids
Include: dronabinol, nabilone. See another part of the chapter.
13.4 Analgesics
Treatment of pain related to cancer is one of the major concerns in oncological patients. Both pain in genital and nongenital parts of the body can keep people from being aroused or feeling pleasure during sexual activity. Chronic pain may cause additional stress, depressive symptoms, or fatigue that indirectly affects sexual desire and genital response. Relieving or diminishing cancer pain usually has a positive impact on patient’s sexuality. On the other hand, physicians should be cautious of potential sexual side effects of different pain medications. The use of more specific methods like appropriate timing, positioning, sensate focus and pelvic muscle relaxation, using lubricants and dilators, and so on may additionally improve sexual pleasure if pain is an issue. Description of these methods is outside of the scope of this chapter and may be found in another part of this book.
Analgesics commonly used in oncology and their impact on sexual health:
· Paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) – aspirin, ibuprofen, diclofenac, naproxen, and so on:
Generally used for mild to moderate pain. No relevant data on the direct impact on sexual functioning. However, chronic use may lead to renal or hepatic insufficiency and related sexual dysfunction.
· Opioids (morphine, fentanyl, codeine, hydromorphone, oxycodone, tramadol):
This group of analgesics is usually reserved for patients with moderate to severe pain or if NSAIDs are not effective. Chronic administration of opioids may lead to symptomatic hypogonadism with fatigue, depressive symptoms, and sexual dysfunction in up to 90 % of patients [8–10]. The possible mechanism involves suppression of gonadotropin release or hyperprolactinemia. Reduction of opioid consumption, inversely, leads to increase in sexual desire and improvement of overall sexual functioning. When chronic opioid administration is mandatory for the well-being of male patients, testosterone supplementation should be considered, if oncologically not contraindicated. Tramadol, due to its serotoninergic properties, prolongs ejaculatory latency time and may cause delayed ejaculation or anorgasmia.
· Antidepressants and anticonvulsants:
Both groups are used for the treatment of pain resistant to other medication and specifically for neuropathic pain with its tingling or burning sensations. Antidepressants sexual adverse events are described in the depression treatment section of this chapter. The literature on sexual dysfunction related to anticonvulsants with pain-relieving properties (e.g., carbamazepine, gabapentin, phenytoin) is scarce and limited mainly to neurologic and psychiatric populations. Carbamazepine and phenytoin increase hepatic synthesis of sex-hormone-binding globuline (SHBG) and therefore may reduce testosterone bioavailability and cause symptoms related to hypogonadism. Data on oxcarbazepine are inconsistent with both improvement of sexual functioning (especially when switching from carbamazepine) but also case reports on occurrence of SD such as anorgasmia or retrograde ejaculation. Case reports of patients treated with gabapentin include ED, anorgasmia, loss of ejaculation, and decreased desire [11, 12].
· Corticosteroids (prednisone, dexamethasone):
Used to decrease swelling which often causes pressure and pain. For sexual side effects, see another section.
· Cannabinoids:
In some countries, allowed in the third-line treatment of cancer pain if other medication is not effective. For sexual side effects, see another section.
13.5 Corticosteroids
Corticosteroids, particularly cortisone and dexamethasone, are used in cancer patients for many different indications. They are a major component in the first phase of leukemia/lymphoma treatment. They are also used for prevention of nausea and vomiting or allergic reactions caused by chemotherapy drugs, for edema reduction (especially for brain, spinal cord, or bone tumors), to increase appetite, and so on. The most common side effects include weight gain, fluid retention, upset stomach, sleep difficulties, and increased blood glucose levels. Decreased libido was reported in 58 % and erectile disturbance in 52 % of patients on steroids. Moreover, total, free, and bioavailable serum testosterone were significantly lower than in controls, while SHBG levels stayed unchanged [13]. Patients on long-term corticosteroid treatment have increased risk of diabetes and neuropsychiatric disorders with a variety of related sexual concerns and dysfunction. Corticosteroid-derived lipodystrophy may also seriously affect body image and therefore patient’s sexuality. Women undergoing treatment with cortisone may experience changes in the menstrual cycle, and reduced fertility.
13.6 Cannabinoids
In many countries, cannabinoids are still not registered for medical use and often perceived as taboo by many health care professionals. Certain cannabinoid drugs have been approved by the Food and Drug Administration (FDA) to relieve nausea and vomiting and to increase appetite in people with cancer. Dronabinol and nabilone are indicated for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetics. Other oncological benefits of cannabinoids that are under research include pain relief, reducing severity of glaucoma (by decreasing pressure within the eyes) and protective effect against the development of certain types of tumors. The impact of prescription drug forms of THC on sexual health has still not been investigated. Increased heart rate, decreased blood pressure, dizziness, fainting, drowsiness, and mood changes were reported by some patients. Sexual side effects have been studied only in recreational marijuana users and with conflicting results. Cannabinoid receptors (CB1) were found in hypothalamus, testes, and ovaries and THC is thought to inhibit binding of dihydrotestosterone to androgen receptor. Decreased plasma testosterone and LH concentrations were reported in chronic marijuana users by some authors while others have not confirmed these findings [14–16]. Apparently, sexual effects of cannabis are dose-dependent. Chronic and high-dose consumption may decrease sexual functioning, while mild to moderate use seems to increase sensuality, erotic feelings, and openness (effect of relaxation).
Key Messages
· Adjuvant medication commonly used in cancer patients may influence their sexual functioning.
· Depression is very common and should always be treated in patients with cancer. ADs with fewer sexual side effects might be preferred along with psychotherapy and psychosocial or supportive interventions.
· Out of the many antiemetics, 5-HT3 receptor antagonists seem to be the safest option in terms of sexual function preservation.
· Effective pain management has a positive influence on sexual functioning.
· Chronic opioid administration may lead to symptomatic hypogonadism.
· Corticosteroid treatment may be associated with SD, especially desire and arousal disorder.
· Medication that negatively influences sexual functioning may often be indispensable but other solutions (PDE-5 inhibitors, hormonal therapies, OTC products, sexual counseling, and rehabilitation) should always be considered to improve the patient´s sexual well-being
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