A Randomized Single Center Trial to Determine the Efficacy of Methadone as a First Line Agent in the Reduction and Treatment of Pain in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation

Mucositis is a normal side effect of stem cell transplant which happens as a result of chemotherapy being given prior to a new donor cell infusion (bone marrow transplant). The chemotherapy will kill cancer cells, but good cells, such as those in the mouth, are killed too. The mouth cells going away causes the areas in the mouth to be blistered, irritated, sore, and extremely painful. Pain medication (usually morphine or hydromorphone if allergic to morphine) are given when oral blisters are seen or felt by patient in patient's mouth. However, one pain medication given through a vein in the patient may or may not be effective and providers are often challenged with providing good pain control while waiting for the new donor cells to grow, which will then heal the mouth. This is a period of waiting that is 6-8 weeks.
The investigators know that methadone, a second pain medication, may decrease pain in a different way than morphine. This is because methadone works in a different way in the brain than morphine. By giving these pain medicines together, the hope of the study is to show decreased pain while waiting for new cells to grow.
The goal of this clinical trial is to hope to learn whether adding methadone (second pain medication) to the current pain medication which is morphine alone (all patients will receive this pain medication) will help reduce the pain experience of participant. Current treatment of morphine alone is sometimes not entirely effective and so any improvement of pain while waiting for new cells to grow is one of the goals of this study. If methadone is effective in decreasing pain, then patients may benefit in the future from using these two medications up front when getting a transplant.
Participant in this study between 6-18 years of age and is needing a stem cell transplant for a disease that can potentially be cured by transplantation.
Participant in this study is receiving chemotherapy and/or radiation conditioning that can cause mucositis. Participants are being asked to participate in this study because participants meet criteria to receive methadone that may or may not reduce pain experience versus just being given morphine alone, which is what all patients are given when the participants have mucositis.
The main goal of the study is to see if less opioid (pain medication) when methadone is added in comparison to participant who uses PCA only. The investigators also want to learn if patient's overall function is improved if given methadone. Another goal would be to see the number of TPN days the participant received and if the participant who was given methadone began to eat sooner. Other smaller goals include learning about side effects of methadone, and if the hospital stay is less for those who receive the study medication.
This medication will be given at Children's Medical Center of Dallas while participant is admitted for the stem cell transplant. There is no sponsor that is funding the study and this drug will be given free of charge in exchange for participation in the study

Start Date01 Jan 2028

Sponsor / Collaborator

The University of Texas Southwestern Medical Center

NCT07365800

/ Not yet recruitingPhase 4IIT

The MDK Study: Using a Combination of Methadone-dexmedetomidine-ketamine for Postoperative Pain Control in Patients Undergoing Complex Spine Surgeries.

This study will investigate whether a combination of three anesthetic medications will reduce intraoperative and postoperative pain in patients undergoing complex spine surgery, and whether it will reduce the use of opioid pain medication after surgery.

Start Date02 Mar 2026

Sponsor / Collaborator

University of Missouri

NCT07226245

/ Not yet recruitingPhase 4IIT

Evaluating Pharmacokinetics of Three Methadone Dosing Strategies During Cardiac Surgery With Cardiopulmonary Bypass

Cardiac surgery frequently leads to significant postoperative pain, with multiple different drug regimens being utilized (both opioid and non-opioid) in an attempt to alleviate this surgical pain. Methadone is currently one of the drugs that is being utilized to help control the pain. It can be given during and/or after surgery. This study hopes to identify the optimal dose of methadone to use to treat this surgical pain.

Start Date01 Mar 2026

Sponsor / Collaborator

Wake Forest School of Medicine

100 Clinical Results associated with Methadone Hydrochloride

100 Translational Medicine associated with Methadone Hydrochloride

100 Patents (Medical) associated with Methadone Hydrochloride

16,751

Literatures (Medical) associated with Methadone Hydrochloride

01 Jun 2026·Addictive behaviors reports

Exploring the effects of cannabidiol on pain sensitivity using quantitative sensory testing among individuals receiving methadone or buprenorphine for opioid use disorder: an open-label, proof-of-concept study

Article

Author: Suh, Rebecca ; Sofuoglu, Mehmet ; De Aquino, Joao P ; Costa, Gabriel P A

While medications for opioid use disorder (MOUD) effectively treat opioid use disorder (OUD), concurrent pain management remains challenging. Cannabidiol (CBD) shows promise in both pain management and OUD treatment. This open-label, proof-of-concept study aimed to evaluate the safety and tolerability of cannabidiol (CBD) and explore its utility for pain sensitivity using quantitative sensory testing (QST) among individuals with co-occurring OUD and chronic pain. Seven individuals with OUD receiving methadone or buprenorphine and experiencing chronic pain completed three test sessions with ascending oral CBD doses (400 mg, 800 mg, 1200 mg). QST analyses for pain sensitivity showed no significant main effects of CBD dose or time but revealed a significant MOUD x CBD dose interaction for heat pain threshold and tolerance. Post-hoc comparisons indicated that participants receiving buprenorphine exhibited significantly higher heat threshold (400 mg) and heat tolerance (800 mg) compared to those receiving methadone. Descriptively, the 400 mg CBD dose was associated with the most favorable pain response patterns across several QST measures in the buprenorphine group. CBD was well-tolerated across all doses; no serious adverse events, changes in subjective effects, or adverse cognitive effects on verbal memory were reported. In conclusion, this pilot study offers preliminary indications that CBD's impact on pain sensitivity varies by dose and MOUD type, notably with potential benefits at 400 mg for individuals on buprenorphine. Coupled with its demonstrated safety and tolerability, these findings support future larger, placebo-controlled randomized trials to confirm CBD's therapeutic utility for pain in this population.

01 May 2026·Journal of substance use and addiction treatment

Differences in take-home methadone receipt by state policy and individual social factors in a multistate survey of people who use drugs: A cross-sectional study

Article

Author: Sugarman, Olivia K ; Harris, Samantha J ; Krawczyk, Noa ; Bandara, Sachini ; Saloner, Brendan ; Taylor, Jirka

BACKGROUND:

Methadone is a highly effective, strictly regulated medication to treat opioid use disorder. COVID-19 flexibilities allowed for up to 28 days of take-homes versus daily travel to clinics for observed dosing, but receiving take-homes differed widely across clinics and individuals. We examined the relationship between state take-home policies and social vulnerability on take-home methadone receipt and days' supply.

METHODS:

Data were from the VOICES study, a telephone survey conducted between 1/2023-8/2024 of people who use drugs from Wisconsin, Michigan, New Mexico, and New Jersey. We estimated average marginal effects of state methadone policy (flexibility-adoption vs non-adoption) on methadone take-home receipt and days' supply. Models were fully adjusted for individual sociodemographic characteristics.

RESULTS:

Most participants were recruited from flexibility-adoption states (n = 285/428, 67%). Over half received take-home methadone (65%; average 3.1 days' supply, SD 6.2); 19% of take-home recipients (n = 54) received ≥3 days' supply. Take-home receipt was higher for participants in flexibility-adoption states (AME 0.52, p < 0.0001). Receiving ≥3 days' supply was lower in people reporting unemployment (vs. employment, AME -0.23, p = 0.0032) and past 30-day drug use (vs. no drug use, AME -0.23, p = 0.0014).

CONCLUSIONS:

State take-home policy was most strongly associated with take-home methadone receipt. Receiving longer days of take-home supplies remains rare. Take-home eligibility guidelines should be established and consider potential social vulnerability factors to daily on-site dosing.

01 May 2026·Journal of substance use and addiction treatment

Treatment of opioid use disorder in pregnancy among individuals with and without co-occurring stimulant use disorder: A retrospective cohort study

Article

Author: Smid, Marcela C ; Charron, Elizabeth ; Tak, Casey ; Gordon, Adam J ; Allshouse, Amanda A ; Cochran, Gerald ; Campbell, Kristine A

INTRODUCTION:

Opioid use disorder (OUD) exists in approximately 1% of US pregnancies and is associated with increased risk of severe maternal morbidity and mortality. Many pregnant individuals with OUD also have a stimulant use disorder (StUD), but it is unclear whether this co-occurring condition changes the types of treatment services they receive. We compared treatment services received during pregnancy between individuals with both OUD and StUD and those only with OUD.

METHODS:

A retrospective cohort study used 2014-2017 data from the Utah All-Payer Claims Database. The sample included pregnancies ≥20 weeks' gestation among individuals aged 15-49 years with ≥4 weeks of insurance enrollment and excluded pregnancies with outcome events occurring <28 weeks after the estimated conception date. Identification of OUD and StUD relied on ICD-9/10 diagnosis codes. Outcomes were receipt of (1) medication for OUD (MOUD; formulations of buprenorphine or methadone administration), (2) outpatient psychosocial services (evaluation and management/assessment services and psychotherapy/counseling or other psychosocial visits), and (3) higher-intensity treatment (intensive outpatient, partial hospitalization, or residential treatment). Logistic generalized estimating equation models, adjusted for demographic and clinical covariates, estimated odds of receiving each service and any service overall.

RESULTS:

Among 146,239 insurance beneficiaries, we identified 1206 pregnancies with OUD, including 305 (25.3%) with co-occurring StUD and 901 (74.7%) only with OUD. Pregnant individuals with StUD and OUD compared to those only with OUD had lower odds of receiving MOUD (adjusted odds ratio [aOR], 0.68; 95% CI, 0.48-0.96) and higher odds of receiving psychotherapy/counseling or other psychosocial visits (aOR, 2.73; 95% CI, 2.01-3.71) and higher-intensity treatment (aOR, 3.47; 95% CI, 1.58-7.59). There were no differences between groups in receipt of evaluation and management/assessment services (aOR, 0.97; 95% CI, 0.83-1.14) or of any treatment service overall (aOR, 1.07; 95% CI, 0.94-1.21).

CONCLUSIONS:

In this sample of Utah insurance beneficiaries, pregnant individuals with co-occurring StUD and OUD were less likely to receive MOUD and more likely to receive psychosocial and higher-intensity services than those only with OUD.

148

News (Medical) associated with Methadone Hydrochloride

24 Feb 2026

·www.drugs.com

Hurricanes Linked to Rise in Drug, Alcohol Deaths Post-Storm

TUESDAY, Feb. 24, 2026 — Hurricanes are terrifying and destructive, but their damage doesn’t end with homes flattened and cities flooded, a new study says. A wave of alcohol- and drug-related deaths also occur in the wake of hurricanes and tropical storms, researchers reported Feb. 20 in JAMA Network Open . Further, these deaths increase as people are exposed to more and longer storms. “Among U.S. counties exposed to tropical cyclones from 1988 to 2019, each additional cyclone-exposed day per month was associated with an increase in psychoactive drug-related death rates,” concluded a team led by Raenita Spriggs , a doctoral student at Columbia University Mailman School of Public Health in New York City. “The associations were greatest in the month of exposure and, in some cases, persisted for up to three months post cyclone,” the researchers found. These results are disturbing, given that such storms are growing in number and intensity due to climate change, said Dr. Manassa Hany , director of addiction psychiatry at Zucker Hillside and South Oaks hospitals at Northwell Health in New York City, who reviewed the findings. “We've always anecdotally suspected that this is the case — if there is a large-scale disaster happening somewhere; that it will lead to problems with substance use disorder and mental health in general,” Hany said. He was not involved in the research. For the new study, researchers analyzed nearly 800,000 substance-related deaths in more than 1,250 U.S. counties that experienced a tropical storm from 1988 to 2019. Results showed that for every day a storm wreaked havoc on a county, the substance-related death rate increased by 3.8% both that month and the month after. Interestingly, only wealthier counties were affected by this increase in substance-related deaths, researchers found. “Lower poverty, predominantly white communities have greater access to prescription drugs, higher rates of prescription drug misuse concurrent with illicit drug use, and higher rates of substance use disorders, which may increase the risk of misuse or overdose when health care systems are disrupted and prescriptions become unmonitored,” researchers wrote. “Additionally, individuals with higher socioeconomic status are more likely to use tranquilizers (e.g., Xanax ), stimulants (e.g., cocaine), and alcohol,” the team continued. “The ability to purchase and access these substances may be greater in wealthier communities, and disruptions in local drug markets during and after cyclones may increase reliance on more dangerous or adulterated substances.” There are a couple of potential explanations why tropical storms might cause an increase in deadly alcohol and drug use, Hany said. These storms cause considerable anxiety and stress, leading some to self-medicate with drinking and drugs, he said. “People may crave something to enter their system and calm them down and numb their feelings,” Hany said. “For those who have substance use disorders and recovery or preexistent substance use disorders, it will promote relapse.” Hurricanes also can disrupt addiction services like treatment centers, Hany said. “If [someone is] getting methadone from an opioid treatment program, it would shut down. If someone is getting suboxone from their doctor, they probably will lose access to that treatment,” he said. “During the time of a natural disaster, people will not be receiving formal treatments such as counseling and group sessions. Their usual treatment process and support will be interrupted.” Hany said that interruption can promote drug cravings that could lead to overdoses. “People may also lose access to naloxone to revive people if an overdose happens because of a severe weather event,” he said. These results show that substance use and mental health services need to be integrated into disaster response plans, researchers said. Hany agreed. “When we prepare for a disaster, we must make sure that people are safe and have a place to shelter, but also make sure that we plan for higher rates of overdose,” Hany said. “When an area is going to be hit with severe weather, we need to make sure the shelters have harm reduction resources such as Narcan, first responders, community aid organizations. We need to equip them.” Sources JAMA Network Open, Feb. 20, 2026 Dr. Manassa Hany, director of addiction psychiatry, Zucker Hillside and South Oaks hospitals, Northwell Health, New York City

04 Feb 2026

·www.drugs.com

RFK Jr. Expands Faith-Based Addiction Care as Drug Use and Homelessness Rise

WEDNESDAY, Feb. 4, 2026 — Amid mounting drug use and homelessness in U.S. cities, Health Secretary Robert F. Kennedy Jr . said the federal government is overhauling the way it fights addiction. The strategy announced Monday includes a new focus on faith-based recovery programs and increased access to medication treatment. Kennedy announced plans to open federal funding to religious organizations that provide addiction care, while launching new programs aimed at helping people who are homeless and struggling with mental illness or substance use get long-term support. Kennedy, who has spoken openly about overcoming a 14-year heroin addiction with help from 12-step programs, said the current health system has often caused people to “cycle endlessly between sidewalks, emergency room visits, jails and mental hospitals and shelters.” He said substance use plays a major role in homelessness and called for more intensive recovery programs that help people learn how to live in the community and find jobs. Kennedy said that he had seen many people turn their lives around in “sober homes and recovery houses.” As part of the plan, federal funding, including state opioid response grants, will now be open to faith-based organizations. “We are bringing faith-based providers fully into this work,” Kennedy said. “This is a chronic disease. It’s a physical disease, it’s a mental disease, it’s emotional disease, but above all, it’s spiritual disease. And we need to recognize that and faith-based organizations play a critical role.” At the same time, Kennedy announced a major expansion of access to medications for opioid use disorder. States and native tribes will be allowed to use federal child protection funds to help addicted parents receive treatments like buprenorphine , methadone and naltrexone . The goal? To keep families together and avoid the need for children to enter foster care. Dr. Yngvild Olsen , formerly with Substance Abuse and Mental Health Services Administration, told The New York Times that the change “has the potential to save lives.” Kennedy also introduced a new $100 million pilot program called STREETS, an acronym for Safety Through Recovery, Engagement and Evidence-Based Treatment and Supports. The program is designed for people who are homeless and living with addiction or serious mental illness. “We’ll engage people continuously, from first contact on the street through recovery, through employment and through self-sufficiency,” Kennedy said. “Law enforcement, courts, housing providers and health care systems will work as one team, so people will no longer fall through the cracks.” He also announced a $10 million grant to expand assisted outpatient treatment, which allows courts to require people with serious mental health issues to receive care in the community. Tom De Vries , president of Citygate Network, which represents about 330 Christian rescue missions, said many faith-based groups are adjusting to the opportunity of receiving federal support. “The government has reached out to us and invited us into the process more than we had been previously,” he said, adding that some organizations are weighing funding opportunities against restrictions on religious practices — for instance hiring only Christians. The administration is also moving away from the government’s long-standing “Housing First” approach. It focused on placing people in permanent housing and then offering, but not mandating, treatment. Rev. Andy Bales , former CEO of the Union Rescue Mission in Los Angeles, said faith-based providers were often shut out under that system. “They wrote us off,” he told The Times . “It was brutal.” Bales also warned that recent Trump administration policy shifts threatened to send up to 170,000 formerly homeless people back onto the streets. “It not only scared stakeholders, but it caused Republican senators to intervene and say, ‘This is too aggressive,’ ” he said. “I don’t think it’s going to be rolled out successfully unless the tone changes, and there is some compromise and diplomacy carried out.” Sources The New York Times, Feb. 2, 2026

09 Jan 2026

·www.drugs.com

Benefit of Retention on MOUD Treatment Lasts for at Least Four Years

FRIDAY, Jan. 9, 2026 -- The benefit of retention on medication for opioid use disorder (MOUD) on overall survival persists through about four to five years of treatment, according to a study published online Jan. 8 in Addiction . Corey J. Hayes, Pharm.D., Ph.D., M.P.H., from the University of Arkansas for Medical Sciences in Little Rock, and colleagues estimated how the risk for all-cause mortality changes with the duration of MOUD in a retrospective cohort study using electronic health record data from the U.S. Veterans Healthcare Administration. The duration of MOUD was measured in days; discontinuation was defined as a gap exceeding 28 days in any MOUD coverage. The sample included 19,666 buprenorphine initiators, 8,675 methadone initiators, and 4,007 extended-release naltrexone initiators. The researchers observed 26,841 discontinuations during approximately 226,000 person-years of time at risk for discontinuation or pre-discontinuation death (118.9 discontinuations per 1,000 person-years). There were 3,251 deaths during a total of about 106,000 person-years of post-discontinuation follow-up (3.1 deaths per 1,000 person-years). The largest marginal gain in probability of six-year survival from an additional year on MOUD occurred around two years compared with six months on MOUD. Relative to six-month MOUD retention, statistically significant gains continued through about four to five years of MOUD retention. After four to five years, there was no statistically significant marginal gain from one additional year of MOUD. "Patients and providers will value these gains differently and our work can help guide discussions on how to optimally choose duration of therapy based on expected survival while accommodating individual values," the authors write. Abstract/Full Text

Clinical Result

100 Deals associated with Methadone Hydrochloride

External Link

KEGG	Wiki	ATC	Drug Bank
D02102	Methadone Hydrochloride	N07BC02	DB00333

R&D Status

Approved

10 top approved records.

to view more data

Indication	Country/Location	Organization	Date
Cancer Pain	Japan	Shionogi & Co., Ltd.	01 Mar 2013
Opioid-Related Disorders	China	Central Pharmaceutical JSC No. 3	01 Jan 1997
Opioid abuse	United States	Hikma Pharmaceuticals USA, Inc.	14 Mar 1973
psychological symptoms behavior compulsive behavior addiction	United States	SpecGx LLC	14 Mar 1973
psychological symptoms behavior compulsive behavior addiction	United States	Hikma Pharmaceuticals USA, Inc.	14 Mar 1973
Opium Dependence	United States	Mylan Institutional LLC	13 Aug 1947
Pain	United States	Mylan Institutional LLC	13 Aug 1947

Developing

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Diabetic Neuropathies	Phase 2	-	Methapharm, Inc.	01 Jan 2012

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04214834 (Pubmed \| J Pediatr)	Phase 3	Neonatal Abstinence Syndrome	189	morphine or methadone (15% decrements)	dzyahuvvms(hhymmqfpvp) = tjyesniook ugotppuvgw (dmmlpkuoal, 7.2 - 9.5)	Positive	01 May 2026
				morphine or methadone (10% decrements)	dzyahuvvms(hhymmqfpvp) = lhiudtidxq ugotppuvgw (dmmlpkuoal, 9.7 - 12.9)
NCT02025855 (CTgov)	Phase 4	Opioid-Related Disorders \| Delirium	9	Methadone (Methadone)	tmwsngylqs(wsgidbnbby) = yywhqhfjlt pcfyqyjlkl (pvtqgoucss, zgtfvkrdek - wqugapwrdp) View more	-	05 Dec 2025
				Placebo (Placebo)	tmwsngylqs(wsgidbnbby) = wwdtpzpopj pcfyqyjlkl (pvtqgoucss, poqqcxtudu - ckddszgmng) View more
NCT03726268 (OSPREy, CTgov)	Phase 4	Pain, Postoperative	907	Methadone (Short-stay, IV Methadone)	kkurvzenpe(ddwawbqcvf) = ubxlkjmdjs xqpwgvyzvr (ldnlhuhhyi, 15.50) View more	-	19 Nov 2025
				Fentanyl+Hydromorphone+Sufentanil+Morphine (Short-stay, IV Short-acting Opioids)	kkurvzenpe(ddwawbqcvf) = shgvdjvrox xqpwgvyzvr (ldnlhuhhyi, 11.60) View more
DUNE (ESMO2025)	Not Applicable	Cancer Pain	136	Methadone	ojgitnxafd(dwxhtnmmuc) = iivbmooaxg gvvgylufdm (neizzzzxdn ) View more	Positive	17 Oct 2025
NCT06110546 (IMPACTOR, CTgov)	Phase 4	-	2	Methadone group (Methadone Group)	cnkgokfsey = llecdtqzjm njsoaaoggi (yommjfpddt, xrlzyhgkkd - omqlzziedz) View more	-	01 Aug 2025
				Usual care (Non-Methadone Group)	ltfoghrhtx(xysdpzeeoj) = rfzdcypynh kzxlahwfmo (mzxijmloae, jezbqcpmvs - vadidcnqdi) View more
NCT05445856 (EudraCT ID 2022-002496-11, Pubmed \| BJA Open)	Phase 4	-	120	Methadone	bgfofcmess(cpvyjqqjrs) = cmbxrlrftp wmhctzepwk (wnwsminmvt, 10 - 50)	Positive	01 Jun 2025
				Fentanyl	bgfofcmess(cpvyjqqjrs) = kkbxeasczr wmhctzepwk (wnwsminmvt, 29 - 80)
NCT04214834 (CTgov)	Phase 3	Neonatal Abstinence Syndrome	189	methadone+morphine (Rapid Wean)	ikihiepaez(vxowozlpgf) = xsqxqpypax wsfjeqtqwn (bqzpkdbmoa, 6.3) View more	-	13 Mar 2025
				methadone+morphine (Slow Wean)	ikihiepaez(vxowozlpgf) = wagsiqkapb wsfjeqtqwn (bqzpkdbmoa, 6.1) View more
NCT05425420 (MTH02, CTgov)	Phase 1/2	Pain, Postoperative	22	Methadone	izxcgxukbk(rbqezdtyth) = baskkkcser oocmsgoobq (zbypceubdu, 1.42) View more	-	10 Feb 2025
NCT05244226 (CTgov)	Phase 2	Sleep Apnea, Obstructive \| Tonsillitis \| Pain, Procedural	66	Hydromorphone+Fentanyl	yywrzqqzds(socigoyenf) = eebbnnpzmc olrzqbaxta (ytniblbxhy, pojwajhdev - hqfviazzwj) View more	-	17 Oct 2024
NCT03033732 (Pubmed \| HIV Med)	Phase 4	Opioid abuse	272	Methadone	piwhziyqfo(wjhcpkbnnt) = utdwsunluk lkhexajpjs (zftxckyxmq ) View more	Positive	01 Jul 2024
				Buprenorphine/naloxone	piwhziyqfo(wjhcpkbnnt) = lbnwgxfjkg lkhexajpjs (zftxckyxmq ) View more

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

AI Agents Built for Biopharma Breakthroughs

Accelerate discovery. Empower decisions. Transform outcomes.

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis