The American Society of Pain and Neuroscience (ASPN) Best Practices and Guidelines for the Interventional Management of Cancer-Associated Pain.

Moderate to severe pain occurs in many cancer patients during their clinical course and may stem from the primary pathology, metastasis, or as treatment side effects. Uncontrolled pain using conservative medical therapy can often lead to patient distress, loss of productivity, shorter life expectancy, longer hospital stays, and increase in healthcare utilization. Various publications shed light on strategies for conservative medical management for cancer pain and a few international publications have reviewed limited interventional data. Our multi-institutional working group was assembled to review and highlight the body of evidence that exists for opioid utilization for cancer pain, adjunct medication such as ketamine and methadone and interventional therapies. We discuss neurolysis via injections, neuromodulation including targeted drug delivery and spinal cord stimulation, vertebral tumor ablation and augmentation, radiotherapy and surgical techniques. In the United States, there is a significant variance in the interventional treatment of cancer pain based on fellowship training. As a first of its kind, this best practices and interventional guideline will offer evidenced-based recommendations for reducing pain and suffering associated with malignancy.

Preventing Post Dural Puncture Headache after Intrathecal Drug Delivery System Implantation Through Preventive Fibrin Glue Application: A Retrospective Study.

BACKGROUND: Cerebrospinal fluid (CSF) leakage resulting in post dural puncture headache (PDPH) is a frequent adverse effect observed after intrathecal drug delivery system (IDDS) implantation. CSF leakage symptoms negatively affect patient quality of life and can result in additional complications. Fibrin glue was used to treat CSF leakage syndrome. We developed a procedure to reduce the incidence of PDPH by preventing CSF leakage with the use of fibrin glue during surgery. OBJECTIVES: The main outcome criterion for this study was the incidence of PDPH syndrome after IDDS implantation with or without preventive fibrin glue application during the procedure. STUDY DESIGN: We designed a monocentric retrospective cohort study to compare the incidence of PDPH due to CSF leakage syndrome after lumbar puncture in patients with an implanted intrathecal pump, with or without preventive fibrin glue application during the procedure. SETTING: The study was held in the Anesthesiology and Pain department of the  Integrative Cancer Institute (ICO), Angers - France. METHODS: The study compared 2 patient cohorts over 2 successive periods. Fibrin glue was injected into the introducer needle puncture pathway after placement of the catheter immediately following needle removal. RESULTS: The no-glue group included 107 patients, whereas the glue group included 92 patients.Two application failures were observed (2.04%). Fibrin glue application results in a significant decrease in PDPH incidence, from 32.7% in the no-glue group to 10.92 % (P < 0.001) in the glue group. In regard to severity, in the no-glue group, 37.1% of PDPH syndromes were mild, 34.3% were moderate, and 28.6% were severe. In the fibrin glue group, 80% of PDPH syndromes were mild, and 20% were moderate. No severe PDPHs were reported after fibrin glue application. Duration of symptoms was also statistically shorter in the fibrin glue group (maximum of 3 days vs. 15 days in the no-glue group). In a univariate analysis, preventive fibrin glue application and age are significant to prevent PDPH. In multivariate analysis, only fibrin glue application was statistically significant (odds ratio, 0.26; P = 0.0008). No adverse effects linked to fibrin glue were observed. LIMITATIONS: The main limitation of this study is its retrospective nature. In addition, this study is from a single center with a potential selection bias and a center effect. CONCLUSIONS: The novel use of fibrin glue is promising in terms of its effect on PDPH and its safety profile. Its moderate cost and reproducibility make it an affordable and efficient technique.

Assessment of Health Care Utilization and Cost of Targeted Drug Delivery and Conventional Medical Management vs Conventional Medical Management Alone for Patients With Cancer-Related Pain.

Importance: Targeted drug delivery (TDD) has potential for cost savings compared with conventional medical management (CMM). Despite positive clinical and economic evidence, TDD remains underused to treat cancer pain. Objective: To assess the cost of TDD and CMM in treating cancer-related pain. Design, Setting, and Participants: This retrospective economic evaluation using propensity score-matched analysis was conducted using MarketScan commercial claims data on beneficiaries receiving TDD and CMM or CMM only for cancer pain from January 1, 2009, to September 30, 2015. Participants were matched on age, sex, cancer type, comorbidity score, and pre-enrollment characteristics. Data analysis was performed from June 1 to September 30, 2017. Main Outcomes and Measures: Total 2-, 6-, and 12-month costs, number of health care encounters, length of hospital stay, additional components of cost, and health care utilization. Results: A total of 376 TDD and CMM patients (mean [SD] age, 51.88 [9.98] years; 216 [57.5%] female) and 4839 CMM only patients (mean [SD] age, 51.52 [11.16] years; 3005 [62.1%] female) were identified for study inclusion. After matching, 536 patients were included in the study: 268 patients in the TDD and CMM group and 268 in the CMM only group. Compared with CMM only, TDD and CMM was associated with mean total cost savings of $15 142 (95% CI, $3690 to $26 594; P = .01) at 2 months and $63 498 (95% CI, $4620 to $122 376; P = .03) at 12 months; cost savings at 6 months were not statistically different ($19 577; 95% CI, -$12 831 to $51 984; P = .24). The TDD and CMM group had fewer inpatient visits (2-month mean difference [MD], 1.0; 95% CI, 0.8-1.2; P < .001; 6-month MD, 1.3; 95% CI, 0.8-1.7; P < .001; 12-month MD, 2.3; 95% CI, 1.2-3.4; P < .001) and shorter hospital stays (2-month MD, 6.8 days; 95% CI, 5.0-8.7 days; P < .001; 6-month MD, 6.8 days; 95% CI, 3.1-10.5 days; P < .001; 12-month MD, 10.6 days; 95% CI, 2.9-18.3 days; P = .007). Use of CMM only was associated with greater opioid use at 12 months (MD, 3.2; 95% CI, 0.4-6.0; P = .03). Conclusions and Relevance: Compared with CMM alone, TDD and CMM together were associated with significantly lower cost and health care utilization. The findings suggest that TDD is a cost-saving therapy that should be considered in patients with cancer for whom oral opioids are inadequate or produce intolerable adverse effects and should be expanded as health care systems transition to value-based models.

Interventional Anesthetic Methods for Pain in Hematology/Oncology Patients.

This article reviews anesthetic interventional approaches to the management of pain in hematology and oncology patients. It includes a discussion of single interventions including peripheral nerve blocks, plexus injections, and sympathetic nerve neurolysis, and continuous infusion therapy through implantable devices, such as intrathecal pumps, epidural port-a-caths, and tunneled catheters. The primary objective is to inform members of hematology and oncology care teams regarding the variety of interventional options for patients with cancer-related pain for whom medical pain management methods have not been effective.

Upper Antero-Medial Thigh as an Alternative Site for Implantation of Intrathecal Pumps: A Case Series.

INTRODUCTION: Neuraxial drug delivery via intrathecal drug delivery systems (IDDS) is becoming an increasingly common mode of treating intractable cancer-related pain, chronic pain, or severe spasticity. An implanted infusion pump delivers medication into the intrathecal (subarachnoid) space via a thin catheter. These pumps are commonly placed in the anterior abdominal wall. Certain conditions may render it difficult or unsafe for an IDDS to be implanted at the traditional site; thus, alternative sites have been explored. We report on the use of the upper antero-medial thigh as a safe alternative site for this purpose. METHODS AND MATERIALS: Nine patients between 22 and 69 years of age underwent placement of an IDDS infusion pump in the upper antero-medial aspect of one thigh. In each patient, the anterior abdominal wall was precluded for implantation due to various reasons, such as extensive abdominal scar tissue from previous surgeries, placement of feeding tubes and ostomies, large ventral hernia or metastatic masses protruding from the abdomen. RESULTS: Nine patients, with ages ranging from 22 to 69 years old, had IDDS implantation in the upper thigh. The first patient experienced wound dehiscence (antero-lateral location) and after explantation, another pump was placed successfully in the opposite thigh (antero-medial location). One patient has had pump replacement due to end-of-battery life. She also needed an unrelated catheter revision. Seven patients have expired from their disease progression after living for an average of 142.7 days (range 50 days to 354 days) while two patients continue to experience relief from pain and spasticity years later (see Table 1). No neurovascular damage, infections, or other complications occurred in our series. CONCLUSION: The upper antero-medial thigh is a safe alternative to the anterior abdominal wall for implantation of an IDDS.

A report on the consequences of the first implanted device for long-term analgesia in refractory cancer pain.

BACKGROUND: During the early 1970s, satisfactory long-term treatment of the severe pain associated with metastatic cancer was not available. Spinal cord stimulation introduced a few years earlier in 1967 had not proven to be effective in treating nociceptive pain. We describe our pioneering experience using an implanted device to infuse local anesthetics into the epidural space and provide pain relief to the patient. METHODS: Increasing doses of systemic opioids were unsuccessful in treating the intractable pain of spinal metastases in our patient. We devised an analgesic delivery system by modifying equipment usually used for ventriculoperitoneal shunts. A lumbar epidural catheter was inserted in the patient's spine, then tunneled subcutaneously across the flank to the anterior abdominal wall, and subsequently connected to a modified Ommaya reservoir with ventriculoperitoneal shunt tubing. This was filled with local anesthetic and injected into the patient's epidural space by manual compression. RESULTS: The system was used for several months with intermittent addition of local anesthetic to the reservoir with satisfactory control of the patient's pain. CONCLUSIONS: We describe the first use of an implanted epidural catheter system for long-term relief of pain due to terminal cancer that occurred at Peter Bent Brigham Hospital in Boston. We contend that this event played an important role in the cascade of devices that followed and connect it to the changes in the attitude of health care providers toward treatment of cancer pain.

Brachial Plexus Block for Cancer-Related Pain: A Case Series.

Neoplastic brachial plexopathy (NBP) is caused by a cancerous infiltration into the brachial plexus, presenting often as severe pain in the affected upper extremity. Such pain can be resistant to medical treatment. Invasive interventions such as brachial plexus neurolysis with phenol or cordotomy may result in severe complications including permanent neurological damage and death. Continuous brachial plexus and paravertebral block with local anesthetic have been reported to successfully control pain from NBP, but these techniques are logistically challenging and frequently have catheter-related complications. We report a series of patients who received single-shot brachial plexus blocks with a mixture of local anesthetic and corticosteroid (bupivacaine 0.25% with methyl-prednisolone 20-120 mg) for the treatment of refractory cancer-related pain in the brachial plexus territory, mostly from NBP. Theoretically, such blocks could provide immediate analgesia from the local anesthetic and a longer-lasting analgesia from the slow-release steroids. Responders reported a sustained decrease in their pain (lasting from 2 weeks to 10 months), a significant decrease in their opioid and non-opioid (ketamine, gabapentin) consumption, overall satisfaction with the block, and unchanged or improved function of their limb. The ideal candidate for this procedure is a patient who has pain that is predominantly neuropathic from a lesion within the brachial plexus and with anatomy amenable to ultrasound-guided nerve block. Our case series suggests that, in the appropriately selected patient, this technique can safely and effectively alleviate pain from NBP. The procedure is simple, spares limb function, and can be diagnostic, predicting response to more complex procedures. To the best of our knowledge, this is the first report using this technique for NBP.

Harlequin Syndrome Following Implantation of Intrathecal Pumps: A Case Series.

OBJECTIVE: Harlequin syndrome (HS) is a condition that has been associated with one-sided sympathetic denervation of the face, characterized by contralateral hemifacial flushing and relative hyperhidrosis. Case series associate HS with conditions and procedures, including neuraxial anesthesia, that disrupt unilateral facial sympathetic innervation. However, to the best of our knowledge, this is the first series of HS following implantation of an intrathecal drug delivery system. CASE SERIES: A 37-year-old and 58-year-old female patients with intractable pain from metastatic cancer were scheduled for placement of an intrathecal pump drug delivery system. Thirty minutes after a mixture of hydromorphone, bupivacaine, and clonidine was initiated through the intrathecal pump, both patients developed well-demarcated skin flushing, confined to one side of their face. Patients were not in distress, and physical examination revealed neither focal neurological deficits nor ocular involvement. Postprocedure thoracolumbar spine magnetic resonance imaging (MRI) was done in the first patient and showed no evidence of neuraxial bleeding or spinal cord compression. The flushing gradually faded and eventually disappeared without any untoward effects. CONCLUSION: HS is a condition associated with one-sided sympathetic denervation of the face that can occur after intrathecal pump implantation. An understanding of the pathophysiology of this condition and reassurance are vital factors for successful management of this condition.

The subjective psychoactive effects of oral dronabinol studied in a randomized, controlled crossover clinical trial for pain.

BACKGROUND: Many cannabinoid medications are approved in North America or in phase III trials, such as dronabinol, nabilone, or nabiximols. Little is known about their subjective psychoactive effects when used for pain management. We hypothesized that when used for pain, dronabinol has psychoactive effects in a dose-response relationship, whose peak effects are comparable with smoking marijuana. METHODS: This was a randomized controlled trial of single dose placebo, 10 or 20 mg dronabinol in 30 chronic noncancer pain patients taking opioids and not using marijuana. Participants completed the Addiction Research Center Inventory (ARCI) hourly for 8 hours during 3 monitored sessions. Comparison sample was the ARCI ratings in participants with no pain (N=20), monitored every 30 minutes after smoking a 1.99% THC (low) and a 3.51% (high strength) marijuana cigarette. RESULTS: The 10 and 20 mg dronabinol doses had significantly elevated scores over time on 4/5 subscales versus placebo (P<0.05). Average daily morphine use, total pain relief (TOTPAR), age, sex, and baseline pain level were not significant covariates. ARCI peak effects at 2 hours were similar to peak effects of smoked marijuana at 30 minutes (P=0.80, 10 mg=low strength, 20 mg=high strength). CONCLUSIONS: In pain patients, oral dronabinol has similar psychoactive effects to smoking marijuana. This risk must be considered in any decision to prescribe cannabinoid medications for pain.

Fusiform aneurysms of the lenticulostriate artery.

Lenticulostriate artery aneurysms are rare, can be difficult to diagnoze, and when they rupture they are often associated with deep intraparenchymal hemorrhages. In particular, fusiform, dissecting aneurysms of a distal lenticulostriate artery are extremely rare. Typically, they are usually associated with underlying systemic conditions such as systemic lupus erythematosus, moyamoya disease, and substance abuse. Given their usual small size and location, these aneurysms may be difficult to detect with angiography and can be challenging to treat with either endovascular or microsurgical techniques. We provide background information, review the existing treatment experiences reported in the literature, and present a discussion regarding the optimal management using an illustrative clinical vignette. Parent artery obliteration can be a safe and effective treatment in these rare aneurysms.

Alteration in pain modulation in women with persistent pain after lumpectomy: influence of catastrophizing.

CONTEXT: Persistent pain is common after surgical treatment of breast cancer, but fairly little is known about the changes in sensory processing that accompany such pain syndromes. OBJECTIVES: This study used quantitative sensory testing to compare psychophysical responses to standardized noxious stimulation in two groups of women who had previously undergone breast cancer surgery: women with (n=37) and without (n=34) persistent postoperative pain. METHODS: Participants underwent a single testing session in which responses to a variety of noxious stimuli were assessed. RESULTS: Findings suggested that women with chronic pain after breast cancer surgery display enhanced temporal summation of mechanical pain, deficits in endogenous pain inhibition, and more intense painful aftersensations compared with those without long-term pain. Some of these group differences were mediated by higher levels of pain catastrophizing in the group of women with persistent pain. CONCLUSION: These findings suggest that persistent postoperative pain is associated with alterations in central nervous system pain-modulatory processes. Future treatment studies might benefit from targeting these pain-modulatory systems, and additional studies using functional neuroimaging methods might provide further valuable information about the pathophysiology of long-term postsurgical pain in women treated for breast cancer.

Local anesthetic blockade of peripheral nerves for treatment of neuralgias: systematic analysis.

BACKGROUND: Nerve blocks with local anesthetics have been used in the diagnosis and treatment of neuralgias. Usually these blocks were administered in combination with corticosteroids and other drugs that can be effective by themselves. Although lasting benefits from nerve blocks in neuralgias have long been described, definitive evidence is lacking. We had the following objectives in this systematic review: to analyze the evidence behind the practice of peripheral nerve blockade with local anesthetics in patients with neuralgias and radicular pain syndromes; to assess the duration of pain relief after conduction block resolution; and to evaluate the effectiveness of the treatment of these syndromes with a series of blocks. METHODS: We searched Medline, Embase, narrative reviews, and book chapters. Only articles published in English were collected. The list of 3347 identified articles was reduced to 39 articles that were read entirely, 12 of which met inclusion criteria. RESULTS: Twelve included articles were analyzed. Each can be classified as a single case report or case series; there were no controlled studies among them. Nine reports assessed a single block outcome; all recorded pain relief beyond the duration of conduction blockade. Those 9 reports represented a total of 69 patients, 30 of whom had complete pain relief and 10 had relief ≥50%. Seven reports with the assessment of continuous pain ≥1 week after a single block reported complete or profound pain relief in 11 of 17 patients. All 3 reports with the assessment of a series of blocks in a large number of patients (total of 270) reported overall positive results. CONCLUSION: Because all reviewed articles were only single case reports or case series, no reliable conclusion could be drawn concerning the effectiveness of nerve blocks with local anesthetics in neuralgia. However, 2 features of the analyzed reports-the large magnitude of the effect and the high consistency of the reported outcome-indicate that future research efforts are warranted.

Patients with chronic pain on opioid therapy taking dronabinol: incidence of false negatives using radioimmunoassay.

BACKGROUND: Serum blood toxicology screens are believed to be important to monitor compliance and to identify levels of illicit substances in patients taking opioids for their chronic pain. METHODS: In this study, the authors examine the incidence of tetrahydrocannabinol (THC) in consecutive blood samples of patients given dronabinol. We assessed the incidence of THC in 27 patients who participated in a single-dose, double-blind crossover trial of dronabinol (Marinol capsules), a synthetic Delta9-THC, as part of a larger study, to determine the reliability of the toxicology screening. Subjects were randomly administered 10 mg or 20 mg of dronabinol or placebo over the course of three 8-hour visits for a combined 228 serum blood samples. Levels of THC were quantified using radioimmunoassay. RESULTS: The majority of the samples (57.4 percent) showed presence of study drug as expected. However, 43 samples (42.6 percent) showed no detectable evidence of THC 4 and 8 hours after administration of dronabinol. Five subjects showed lower serum levels on the higher dose (20 mg) than on the lower dose (10 mg) after 4 hours, and two subjects showed lower levels with the higher dose after 8 hours. One subject had no detectable THC on any dose of dronabinol. CONCLUSIONS: These toxicology reports point to higher than anticipatedfalse-negative results with radioimmunoassay blood serum screening. Results could be explained by the lower sensitivity of this screening technique and also in how oral cannabinoids are metabolized. Further investigations are needed on the accuracy of the detection of THC among patients known to have used dronabinol.

Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy.

UNLABELLED: We assessed the efficacy of dronabinol (Marinol capsules; Solvay Pharmaceuticals, Brussels, Belgium), a synthetic Delta(9)-THC (tetrahydrocannabinol), in 30 patients taking opioids for chronic pain to determine its potential analgesic effects as an adjuvant treatment. Phase I of this 2-phase study was a randomized, single-dose, double-blinded, placebo-controlled, crossover trial in which subjects were randomly administered either 10 mg or 20 mg of dronabinol or identical placebo capsules over the course of three, 8-hour visits. Baseline self-report measures, hourly ratings of pain intensity, pain relief, pain bothersomeness, treatment satisfaction, mood, side effects, and blood serum levels were obtained. Phase II was an extended open-label titrated trial of dronabinol as add-on medication to patients on stable doses of opioids. Results of the Phase I study showed that patients who received dronabinol experienced decreased pain intensity and increased satisfaction compared with placebo. No differences in benefit were found between the 20 mg and 10 mg doses. In the Phase II trial, titrated dronabinol contributed to significant relief of pain, reduced pain bothersomeness, and increased satisfaction compared with baseline. The incidence of side effects was dose-related. Overall, the use of dronabinol was found to result in additional analgesia among patients taking opioids for chronic noncancer pain. PERSPECTIVE: This study examines the effect of adding a cannabinoid to the regimen of patients with chronic pain who report significant pain despite taking stable doses of opioids. The results of our preliminary study suggest that dronabinol, a synthetic THC, may have an additive effect on pain relief.

Urine toxicology screening among chronic pain patients on opioid therapy: frequency and predictability of abnormal findings.

OBJECTIVE: To examine the incidence of abnormal urine toxicology screening among chronic pain patients prescribed opioids for their pain and to relate these results to patient descriptors and type, number, and dose of prescribed opioids. METHODS: A retrospective analysis of data from 470 patients who had urine screening at a pain management program in an urban teaching hospital was performed. Urine samples were analyzed using gas chromatography-mass spectrometry. Patients were categorized as having urine screens that were "normal" (expected findings based on their prescribed drugs) or abnormal. Abnormal findings were those of (1) absence of a prescribed opioid, (2) presence of an additional nonprescribed controlled substance, (3) detection of an illicit substance, and (4) an adulterated urine sample. RESULTS: Forty-five percent of the patients were found to have abnormal urine screens. Twenty percent were categorized as having an illicit substance in their urine. Illicit substances and additional drugs were found more frequently in younger patients than in older patients (P<0.001). No other variables were found to predict abnormal urine screen results. DISCUSSION: These results confirm past findings that random urine toxicology screens among patients prescribed opioids for pain reveal a high incidence of abnormal findings. Common patient descriptors, and number, type, and dose of prescribed opioids were found to be poor predictors of abnormal results.

Topical amitriptyline in healthy volunteers.

BACKGROUND AND OBJECTIVES: The antidepressant amitriptyline is used as an adjuvant in the treatment of a variety of chronic pain conditions. This drug interacts with many receptors and ion channels, such as Na+ channels. In a randomized, double-blinded, and placebo-controlled trial, we investigated whether amitriptyline also is capable of providing cutaneous analgesia when applied topically in 14 healthy volunteers. METHODS: Amitriptyline hydrochloride was prepared as a 45% water/45% isopropanol/10% glycerin solution and titrated to pH 8.5 with sodium hydroxide. Four areas, 2 on each arm, of approximately 1 cm(2) each were marked on the ventral aspect of the upper arm. A piece of gauze, placed on each of the marked areas and affixed to the arm with an occlusive plastic dressing, was saturated via syringe with placebo and amitriptyline solutions (10 mmol/L, 50 mmol/L, and 100 mmol/L). After 1 hour, the dressings and gauze were removed. A 16-G blunt needle was used to grade the pain at the marked area once per hour (1 = complete analgesia, 10 = normal pain sensation). RESULTS: The analgesic effects of 50 mmol/L and 100 mmol/L solutions of amitriptyline were significantly higher than those of the placebo or the 10 mmol/L solution. However, no significant difference was found between the analgesia provided by the placebo solution versus the 10 mmol/L solution or between the 50 mmol/L versus the 100 mmol/L solution. The only side effect observed was a concentration-dependent redness of the skin. CONCLUSIONS: Topically applied amitriptyline is effective as an analgesic in humans. Different vehicles may improve its efficacy and decrease the skin redness observed.

Assessment of differential blockade by amitriptyline and its N-methyl derivative in different species by different routes.

BACKGROUND: Increasing the duration of local anesthesia and/or creating greater differential blockade (i.e., selective block of pain-transmitting nerve fibers) has been attempted by modifying currently available agents. Most drugs show a different profile depending on the model or species studied. This study was designed to investigate the differential nerve-blocking properties of amitriptyline and its quaternary ammonium derivative in rats and sheep. METHODS: The Na+ channel-blocking properties of N-methyl amitriptyline were determined with the patch clamp technique in cultured GH(3) cells. Various functions (motor, nociception, proprioception-ataxia) were compared in rats (spinal and sciatic nerve blockade) and sheep (spinal blockade) with amitriptyline, N-methyl amitriptyline, lidocaine, and bupivacaine (partially from historical data). RESULTS: In vitro testing revealed N-methyl amitriptyline to be a potent Na+ channel blocker similar to amitriptyline but with a much longer duration of action. All drug concentrations tested in both the sciatic nerve model and the spinal block model produced no significant differential blockade in rats. Three of six rats in the 20-mM N-methyl amitriptyline group showed residual blockade 4 days after sciatic nerve injection. However, in the sheep spinal model, amitriptyline and in particular N-methyl amitriptyline displayed significant differential blockade at most time points. Sheep data for lidocaine and bupivacaine seemed to be more comparable to the clinical experience in humans than did rat data. CONCLUSIONS: Amitriptyline and N-methyl amitriptyline are potent Na+ channel blockers and show greater differential blockade in sheep than in rats. This differential blockade in sheep is greater than that produced by lidocaine or bupivacaine.