To identify guidelines for implementing intrathecal therapy (IT) and provide considerations for effective analgesia for chronic pain in patients with cancer or others at the end of life

• Authors state that the guidelines are based on available evidence from observational and randomized, prospective trials.
• Databases searched were not reported.
• Search keywords were intrathecal, cancer, palliative, pain, guidelines, opioids, consensus, selection, and evidence.
• Studies were included in the review if they involved patients with cancer-related pain or other end-of-life states causing pain.
• Exclusion criteria were not included.
• No conflicts of interest were identified.

This resource provides a summary of evidence and relevant recommendations regarding patient selection for IT therapy, implications of prior therapy and its results, use of IT pain therapy with concurrent chemotherapy or radiation, implications with epidural metastases, infection, comorbid conditions, social issues, and healthcare coverage.

• Several trials have demonstrated that IT therapy can reduce neuropathic-nociceptive pain while reducing drug-related toxicities and the need for supplementary systemic opioids.
• Despite a lack of robust evidence, clinical experience suggests that patients with poor pain relief or intolerance with systemic opioids can be effectively managed with IT.
• Potential clinical side effects include hyperalgesia, hypotension, sedation, and respiratory depression. Proper monitoring is essential, particularly in the first 24 hours after drug initiation.
• Patient selection should be based on the type of pain, although limited evidence exists in this area. IT may be appropriate for patients with soft tissue cancers with visceral nociceptive pain and pain attributed to bone metastases.
• No confirmed association has been found between patient response to oral opioids and response to IT therapy.
• Systemic infection was identified as a contraindication to device implantation. The authors reviewed evidence from the Centers for Disease Control regarding prophylaxis for surgical site infection. IT has been found to be useful for patients who are immunocompromised.
• Battery drain or electric failure of the implanted device can occur if the pump is directly in the radiation field and shielding. Minimizing radiation exposure or relocating the pump should be considered if the pump is directly in the radiation field.
• IT requires appropriate social support for follow-up and ongoing care. Lack of insurance coverage or social support is a contraindication to device implantation.

Recommendations provided are limited by reliance on consensus and the limited evidence available from clinical trials regarding the application of IT.

Consideration for comorbidities, support systems, compliance with recommended treatment plan, current or prior therapies, incorporation of the oncologist into the treatment plan, psychological monitoring, and appropriate trialing technique are key in the use of IT therapy. The authors advocate for wider application of IT therapy to effectively manage patients experiencing cancer and end-of-life pain.

To assess the effect and tolerability of oral normal-release morphine (NRM) during the initial phase of the treatment of patients with moderate to severe cancer pain

Eligible patients received oral NRM at a starting dose of 5 or 10 mg every four hours. Patients whose pain was not controlled with World Health Organization (WHO) step I analgesics received 5 mg NRM. Patients who received step II therapy received 10 mg NRM. Patients who did not get satisfactory pain relief during the interval between one dose and the next could take rescue doses of oral NRM, up to one dose every hour; rescue NRM doses were the same as the patient’s regular doses. Dose was retitrated on a daily basis so that the dose of oral NRM to be given in the next 24 hours was based on the total opioid dose (regular plus rescue). If possible, patients completed an ambulatory visit for assessment after two and five days from the beginning of the study. On other days, patients received a telephone call that monitored pain intensity, drug dose, and onset of symptoms.

• The sample was composed of 159 patients; 135 completed the study.
• Mean patient age was 65 years. Age range was 29–87 years.
• Of all patients, 34.6% were female and 65.4% were male.
• All patients had advanced cancer. The sample included multiple diagnoses. The pain score of all patients was 5 or higher for at least 24 hours.

• Multisite
• Outpatient
• Sixteen palliative care centers in Italy

Open-label, phase IV clinical trial

• Numeric Rating Scale (NRS) for pain (0 = no pain, 10 = worst pain possible), as reported in each patient's diary
• Mini Mental State Examination (MMSE) (The number of potential subjects who were excluded was fewer than six.)
• Karnofsky Performance Status Score, as reported in each patient's diary
• NRS regarding morphine dosage and adjunct analgesic therapy
• NRM-related adverse events, presence and frequency of episodic pain
• Score on intensity scale, 1–3 (1 = mild, 2 = moderate, 3 = severe), as assigned during physician assessment at visits, to assess safety of NRM

• Of patients categorized as “intent to treat,” or ITT, a very high percentage (45%) achieved pain control for more than 90% of the follow-up period. Of these patients, 79% achieved pain control within 24 hours after taking the first oral NRM dose; 50% of these patients achieved pain control within the first eight hours.
• Most commonly reported adverse events were somnolence (24% of patients), constipation (22%), vomiting (13%), nausea (10%), and confusion (7%). These events occurred primarily in the first days of treatment. With the exception of constipation, none of the events required treatment. Authors observed no unexpected adverse events.

Oral NRM, administered according to European Association for Palliative Care recommendations, can effectively and rapidly decrease pain intensity. In opioid-naive patients, oral NRM has an acceptable safety profile.

• The study had a risk of bias due to no appropriate control group.
• The study was conducted in 16 palliative care units in Italy. Future researchers should repeat the study in a more general setting and in other countries.

This trial demonstrated that clinicians should begin administering NRM as soon as possible to treatment moderate to severe cancer-related pain instead of waiting until the patient is at an advanced or terminal stage. Through titration, the analgesic treatment was tailored to the patient’s needs, and close evaluation and re-evaluation of pain intensity and frequency helped ensure that the therapy continued to be effective and tolerated. Nurses can advocate for NRM when caring for patients with higher levels of pain, thereby increasing the patient’s level of comfort and optimizing patient-centered treatment.

Patients were instructed in six individual one-hour sessions on the use of progressive muscle relaxation (PMR) and were provided with a relaxation tape and written instructions. In addition to relaxation training, the session provided support focused on concerns related to cancer radiation treatment and its effects and on the physical and emotional sensations experienced. During the fourth session, cue-controlled relaxation was presented as an active coping process that included four steps:  PMR, deep breathing, pairing the relaxed state with a self-induced cue word (“calm\"), and coping with tension by self-administration of the cue-controlled relaxation response. During the last session, client concerns about cancer, treatments, stress, and relaxation were reviewed, and further questions were answered. The importance of practicing relaxation regularly at home was emphasized. The control group received usual care.

• Fifty-two women and 30 men scheduled to receive external beam radiation therapy were assigned randomly to the relaxation therapy condition or a control condition.
• Mean age was 61 years (range 37–84).
• The primary disease sites represented were breast (36%), prostate (17.5%), and colon (10%).
• Of the patients, 92% were being treated with curative intent.

Outpatient radiation treatment facility

Patients were undergoing the active treatment phase of care.

The study was a randomized, controlled trial with a usual care control group.

Profile of Mood States (POMS)

Patients receiving relaxation training reported a significant reduction in tension and anger and a trend toward less depression. Comparisons between the relaxation therapy and control groups using MANOVA indicated that there were no statistically significant differences in the pre- and posttest scores for the controls, with the exception of fatigue; patients in the control group became significantly more fatigued (p = 0.01).

• Patient adherence to relaxation exercises at home was unknown.
• Outcome assessors were not blinded to treatment assignment.
• The study had a small sample size, and no power analysis was provided.
• The study design did not include an attention-placebo condition to control for the effects of suggestion and attention.
• The relative importance of the different components of the intervention cannot be known.
• Professional training is required to deliver the supportive care and psychoeducational component of the intervention.

To assess emetic responses to multiday palonosetron, aprepitant, and low-dose dexamethasone among patients treated with pretransplant regimens for multiple myeloma and lymphoma prior to undergoing stem cell transplantation

Oral aprepitant with IV dexamethasone and palonosetron was administered on days -3, -2, -1 for multiple myeloma and days -7 through -5 for patients with lymphoma. The patients with lymphoma also received IV dexamethasone and palonosetron on days -4 and -3.  Palonosetron was repeated on third post transplant day. Patients with multiple myeloma were given melphalan, and patients with lymphoma received BCNU, etoposide, cytarabine, and melphalan with or without rituximab. Patients with multiple myeloma completed questionnaires on days -2, -1, +3, and +7. Patients with lymphoma completed questionnaires on days -6 through -2 and on days +3 and +7. The Common Terminology Criteria for Adverse Events version 3 wascused to evaluate nonhematologic toxicities.

• N = 18  
• AVERAGE AGE = Multiple myeloma group: 60 years (range = 53–66 years), lymphoma group: 48 years (range = 35–60 years)
• MALES: 61%, FEMALES: 39%
• KEY DISEASE CHARACTERISTICS: Six out of nine patients with multiple myeloma reported using pain medications at time of transplantation.
• OTHER KEY SAMPLE CHARACTERISTICS: Most subjects were Caucasian with Karnofsky Performance statuses greater than 60. 

• SITE: Single site    
• SETTING TYPE: Inpatient    
• LOCATION: University of Kansas Medical Center

• PHASE OF CARE: Active antitumor treatment

Nonrandomized, prospective, descriptive cohort design

• Emetic response was assessed by daily patient diaries and the MASCC Antiemesis Tool (MAT).
• Nausea was measured by a 10-point Visual Analog Scale (VAS)
• The Osoba modules were modified by removing retching from the nausea module and adding it to the emetic module.  
• The modified Osoba modules were used to assess impact of CINV on overall quality of life.

Complete control (CC) was achieved in the acute phase by 55% of patients with multiple myeloma and 100% of patients with lymphoma for a combined acute phase CC of 78%. In the delayed phase, CC fell to 22% in the multiple myeloma group and 44% in the lymphoma group. In the extended phase, CC fell to 11% and 22%, respectively. No complete emetic response was noted in either group, and no patients experienced more than five emetic episodes with a 24-hour period. They reported no significant nausea in the acute phase although they could not report on nausea in the delayed and extended phases because of missing data. Overall nausea remained a major problem with 78% of all patients developing some level of nausea.

Nausea and vomiting continued to be problematic for both groups in the post-transplant period, and these data were correlated with worsening Osoba scores. This drug combination was safe, feasible, and effective in the acute phase of CINV. However, other strategies are needed to treat patients scheduled for stem cell transplants.

• Small sample (< 30)
• Risk of bias (no control group)
• Risk of bias (no random assignment)

The results of this study were not strong enough to influence treatment protocols. However, the study did underscore the need to assess patients receiving stem cell transplantations for at least a week for CINV.

To determine if traditional acupuncture (TA) could reduce hot flashes and night sweats (HF&NS) frequency, improve physical and emotional well-being, and improve perceptions of HF&NS in women receiving tamoxifen after active breast cancer treatment.

Women with a diagnosis of breast cancer receiving tamoxifen who reported experiencing HF&NS for more than three months underwent eight sessions of TA, delivered once weekly. They were monitored for 30 weeks, during which there were five measurement points. Data were collected using a paper-based hot flash diary. Physical and emotional well-being were measured using two questionnaires:  the Women’s Health Questionnaire (WHQ) and the Hot Flashes and Night Sweats Questionnaire (HFNSQ).

• The sample was comprised of 47 female patients.  
• Mean age was 54.3 years (range 37–68). 
• Patients
  • Were women taking tamoxifen as adjuvant treatment for early breast cancer
  • Were six or more months postsurgery, chemotherapy, or radiotherapy
  • Were taking tamoxifen for at least six months
  • Reported HF&NS for at least 3 months.
  • Had no recurrent or metastatic disease
  • Could be receiving concomitant preparations for relieving HF&NS, whether prescription or over the counter, if they had been taking them at least three months and would continue them through the trial period.

• Single site   
• Outpatient 
• Mount Vernon Hospital, Middlesex, United Kingdom

• Patients were undergoing the active treatment phase of care.
• The study has clinical applicability for late effects and survivorship.

This was a prospective, single-arm, observational study using before and after measurements.

• Hot Flash Diaries    
• WHQ
• HFNSQ

HF&NS mean frequency was reduced by 49.8% (95% confidence interval [40.5, 56.5]; p < 0.0001; n = 48) at end of treatment (EOT) over baseline. Trends indicated longer-term effects of TA at 4 and 18 weeks after EOT. At EOT, seven WHQ domains showed significant statistical and clinical improvements, including Anxiety/Fears, Memory/Concentration, Menstrual Problems, Sexual Behavior, Sleep Problems, Somatic Symptoms, and Vasomotor Symptoms. Perceptions of HF&NS as a problem were reduced by 2.2 points (standard deviation = 2.15 points; n = 48; t = 7.16; p < 0.0001).

The study supports using TA to manage HF&NS in women receiving tamoxifen as a breast cancer treatment. In addition, it suggests that the women received the added benefit of improved emotional and physical well-being with few side effects.

• The study lacked an appropriate control group.
• The study lacked control over the therapeutic relationship that was established between the practitioner and the patient, which could have contributed to the placebo effect.
• Concomitant medication was used for managing hot flashes.

Nurses should recognize that tamoxifen continues to pose distressing side effects in women with breast cancer, even after prolonged use. This study suggests that, through the use of TA, women receiving tamoxifen may be able to control some of these distressing side effects. Randomized, controlled trials using larger samples are warranted to validate TA as a tool for reducing these common side effects. Future studies, if including concomitant medications for hot flash symptoms, may want to control the types of concomitant medication usage for further analysis of results or have a randomized group to TA alone to TA plus a specific concomitant medication to note if hot flash symptoms are further controlled.

The study compared the effects on shoulder movement and lymphatic disturbance of two exercise schemes after surgery in patients with breast cancer. Subjects were randomly assigned to two exercise groups based on kinesiotherapy: directed group guided by a physiotherapist with a regimen of 19 exercises (exercises were performed 10 times with 60-second intervals between exercises) and free group, which had no defined sequence or number of repetitions. Both groups began with three exercises beginning on the first day after surgery. Exercises were performed in outpatient physiotherapy department. The study was reviewed by the Research Commission and Ethics Committee of the faculty of medical sciences. Patients participated in a 40-minute session three times weekly for a period of 42 days.

• The study sample (N = 60) was comprised of female patients who had undergone modified radical mastectomy or quadrantectomy with axillary dissection for breast cancer.
• Patients were excluded from the study if they
  • Underwent immediate reconstruction
  • Had bilateral breast surgery
  • Had greater than 2 cm difference in arm circumference before surgery
  • Experience any limitation of limb movement prior to surgery
  • Had greater than 20° difference in flexion and abduction before surgery.
  • Were unable to understand proposed exercises.

Patients were recruited from State University of Campinas, Brazil.

• Manual goniometer (no passive support given) was used to measure range of motion.
• Arm circumference was measured using a universal tape measure; measurement points were 7.5 cm above the humeroradial joint and 7.5 cm below the humeroradial joint, at ulnar styloid at wrist, and at metacarpophalangeal joints.
• Demographic data collected along with age, BMI, number of lymph nodes, and number of PT sessions.

No difference in groups was found in terms of individual characteristics and clinical-surgical characteristics. Incidence of infection was similar in both groups. Lymphatic disturbance showed no statistical difference between groups. Incidence of seroma was not statistically different between groups. The directed exercise group had more recovery of range of motion in shoulder in flexion, abduction, and external rotation compared with the free group. Patients who received directed exercises achieved better function and return to premorbid function than those patients who did free exercise.

• The small sample size limits generalizability.
• Access, time, and cost could be patient barriers.
• Comorbidities are not addressed or described.

To determine if the intrathecal analgesia technique is not inferior to continuous epidural (EP) infusions for postoperative pain in patients undergoing liver resections

Patients who had epidural analgesia had catheters inserted at the T9-10 or T10-11 levels. Ropivacaine and morphine were injected prior to anesthesia. In the intrathecal group, a dural puncture was done at the L3-4 or L 5-6 level, and morphine and saline were injected prior to anesthesia. In the EP group analgesia was continued with ropivacaine. In both groups, patients could receive 1 mg boluses of morphine from a patient-controlled IV pump. A value of 10 mm was used to determine noninferiority. Assessments were done at four, eight, 12, 24, 36, and 48 hours.

• N = 50
• AGE = Not provided
• MALES: Not provided        
• FEMALES: Not provided
• KEY DISEASE CHARACTERISTICS: Undergoing liver resection for cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Patients with elevated international normalized ratios or reduced platelet counts were excluded.

• SITE: Single site  
• SETTING TYPE: Inpatient  
• LOCATION: Italy

PHASE OF CARE: Active antitumor treatment

Prospective noninferiority trial

• Morphine consumption
• Visual Analog Scale (VAS) for pain (100 mm assumed but not specified)

The time to first morphine requirement was longer in the epidural group at all time points, and by 48 hours, morphine use in the intrathecal group was four times higher than in the epidural group (p < 0.001). Extubation time and recovery room time were significantly shorter in the epidural group (p < 0.05). The total amount of morphine required in the intrathecal group was higher (p < 0.01). No significant differences between the groups in postoperative pain scores were reported.

Although this study reported that a single dose of intrathecal preoperative analgesia was not inferior to epidural analgesia, other measures reflecting postoperative pain were in favor of epidural analgesia. A single preoperative dose of intrathecal morphine may be a viable alternative approach to manage acute pain.

• Small sample (< 100)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Other limitations/explanation: No demographic information was reported.

The findings of this study suggested that a single intrathecal dose of morphine preoperatively can provide an alternative approach for the management of postoperative pain, which may be useful for patients in whom continuous epidural analgesia is not appropriate.

To assess the efficacy of Uncaria tomentosa (cat’s claw) on quality of life, fatigue, anxiety, depression, and sleep quality in patients with terminal cancer when used in conjunction with monitoring for changes in biochemical and inflammatory parameters

A 100 mg dose of dry extract of Uncaria tomentosa (U tomentosa) was administered orally three times daily for eight weeks.

• N = 51  
• MEDIAN AGE = 64 years (range = 33–85 years)
• MALES: 53%, FEMALES: 47%
• KEY DISEASE CHARACTERISTICS: Solid tumors with no additional therapeutic options; life expectancy greater than two months
• OTHER KEY SAMPLE CHARACTERISTICS: 74.5% white; 19.6% colon; 15.3% breast, 13.7% lung; Karnofsky Performance Status ≤ 80 (65%)

• SITE: Single-site 
• SETTING TYPE: Not specified
• LOCATION: Academic center, Sao Paulo, Brazil

• PHASE OF CARE: End-of-life care
• APPLICATIONS: Palliative care

• Single-center, open-label study
• Prospective, repeated measures

• European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ C30)
• Functional Assessment of Chronic Illness Therapy–​Fatigue (FACIT-F)
• Chalder Fatigue Scale (CFQ)
• Hospital Anxiety and Depression Scale (HADS) 
• Pittsburgh Sleep Quality Index–Brazil (PSQI-BR)

Overall quality of life (p = 0.00411) and social functioning (p = 0.0341) improved. Fatigue as assessed by the CFQ improved (p = 0.0496). No improvement in sleep quality anxiety was determined. There was no change in liver function, kidney function, blood counts, or inflammatory blood parameters.

Managing symptoms in patients with no additional treatment options is important. U tomentosa improved overall quality of life and social functioning and reduced fatigue in patients with cancer who had no additional treatment options. U tomentosa did not affect sleep quality, anxiety, or depression, but it did not alter the inflammatory parameters studied.

• Small sample (< 100)
• Risk of bias (no control group)  
• Risk of bias (no blinding)
• Risk of bias (sample characteristics)
• Findings not generalizable

U tomentosa may be useful in reducing fatigue and improving overall quality of life in patients who have no other treatment options.

To determine whether the average decrease in fatigue from days 1 (baseline) to 21 and from days 21 to 49 was greater in patients who received guarana versus placebo, as measured by Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) scores.

Patients received baseline evaluations with questionnaires, then 50 mg of guarana or placebo twice daily, study questionnaires 21 days later, and a seven-day washout of the drug. Patients were then crossed over to the opposite group for 21 days of the drug, followed by questionnaire completion and toxicity assessment.

• The study included 60 women with breast cancer.
• Mean age was 50.2 years in the placebo-guarana group and 51.76 years in the guarana-placebo group.
• All patients had worsening fatigue on the Brief Fatigue Inventory (BFI) for eligibility and were entered prior to their second cycle of initial chemotherapy.
• Those with severe fatigue were excluded.
   

The study took place in two public and academic hospitals in São Paulo, Brazil.
 

Patients were undergoing the active treatment phase of care.

This was a double-blind, placebo-controlled, randomized, crossover trial.

• General demographic questionnaire    
• FACIT-F
• FACIT-Endocrine Symptoms (FACIT-ES)
• Hospital Anxiety and Depression Scale (HADS)
• Pittsburgh Sleep Quality Index (PSQI)
• Chalder Fatigue Scale

More patients showed improvement in FACIT-F in the guarana group at day 21 (p = 0.01) and day 49 (p = 0.02). Chalder Fatigue Scale scores decreased by 4.6 points on day 21 (p < 0.01), with no significance for day 49 compared to placebo. Sleep improvement was seen at day 49 (p = 0.05). Four patients discontinued guarana use because of tachycardia. Analysis was conducted between groups on specific days of the study, rather than analyzing the intervention condition and control condition as a whole between groups.

Guarana showed a superior effect to placebo in improving fatigue in patients with breast cancer undergoing treatment.

• The study had a small sample size, with less than 100 patients.
• Only one tumor type was used, and common comorbidities were excluded. 
• The statistical analysis was conducted to compare results between groups at days 21 and 49, rather than at a specific time point in the study and analyzing the findings between the experimental and control condition. This is not a meaningful comparison study.
   

Guarana may be an option to treat fatigue in this population, but additional research is needed to provide support for its clinical use. Patients should be cautioned on its use if they have angina, other cardiovascular disease, uncontrolled hypertension, or neurologic disorders.

To evaluate the effectiveness of treating epidermal growth factor receptor–inhibitor (EGFRI)-induced rash using a topical antibiotic or a combination of an antibiotic and benzoyl peroxide for grade 1 rash, or systemic treatment (oral antibiotics) for grade 2 or higher rash eruption.

On initiation of EGFRIs, all patients started sunscreen, a mild skin cleanser, and oatmeal cream daily. Patients with a grade 1 rash were treated with a topical antibiotic or an antibiotic and benzoyl peroxide. Patients with a grade 2 or higher rash eruption were treated with systemic treatment (oral antibiotics).

The study reported on a sample of 19 patients with lung and colorectal cancer who initiated therapy with EGFRI agents (erlotinib or cetuximab) and had skin alterations.

Portugal

This was a prospective, descriptive study.

• Clinical and photographic evaluation
• National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3

• Eighteen of 19 patients developed a grade 2 rash.
• Of those 18 patients, 50% had a complete response to treatment with tetracyclines (mainly doxycycline).
• Only one patient had grade 3 rash, which did not respond to minocycline.
• None of the patients had to stop treatment with EGFRI therapy.

Tetracycline antibiotic treatment, in combination with benzoyl peroxide, was effective in completely resolving EGFRI-induced rash in 50% of the sample.

• This was a small, noncontrolled study.
• A combination of interventions was used; therefore, determining the effectiveness of the individual interventions is difficult.